A robust two-stage design identifying the optimal biological dose for phase I/II clinical trials

We propose a robust two-stage design to identify the optimal biological dose for phase I/II clinical trials evaluating both toxicity and efficacy outcomes. In the first stage of dose finding, we use the Bayesian model averaging continual reassessment method to monitor the toxicity outcomes and adopt an isotonic regression method based on the efficacy outcomes to guide dose escalation. When the first stage ends, we use the Dirichlet-multinomial distribution to jointly model the toxicity and efficacy outcomes and pick the candidate doses based on a three-dimensional volume ratio. The selected candidate doses are then seamlessly advanced to the second stage for dose validation. Both toxicity and efficacy outcomes are continuously monitored so that any overly toxic and/or less efficacious dose can be dropped from the study as the trial continues. When the phase I/II trial ends, we select the optimal biological dose as the dose obtaining the minimal value of the volume ratio within the candidate set. An advantage of the proposed design is that it does not impose a monotonically increasing assumption on the shape of the dose-efficacy curve. We conduct extensive simulation studies to examine the operating characteristics of the proposed design. The simulation results show that the proposed design has desirable operating characteristics across different shapes of the underlying true dose-toxicity and dose-efficacy curves. The software to implement the proposed design is available upon request

Overlapping Indices for Dynamic Information Borrowing in Bayesian Hierarchical Modeling

Bayesian hierarchical model (BHM) has been widely used in synthesizing information across subgroups. Identifying heterogeneity in the data and determining proper strength of borrow have long been central goals pursued by researchers. Because these two goals are interconnected, we must consider them together. This joint consideration presents two fundamental challenges: (1) How can we balance the trade-off between homogeneity within the cluster and information gain through borrowing? (2) How can we determine the borrowing strength dynamically in different clusters? To tackle challenges, first, we develop a theoretical framework for heterogeneity identification and dynamic information borrowing in BHM. Then, we propose two novel overlapping indices: the overlapping clustering index (OCI) for identifying the optimal clustering result and the overlapping borrowing index (OBI) for assigning proper borrowing strength to clusters. By incorporating these indices, we develop a new method BHMOI (Bayesian hierarchical model with overlapping indices). BHMOI includes a novel weighted K-Means clustering algorithm by maximizing OCI to obtain optimal clustering results, and embedding OBI into BHM for dynamically borrowing within clusters. BHMOI can achieve efficient and robust information borrowing with desirable properties. Examples and simulation studies are provided to demonstrate the effectiveness of BHMOI in heterogeneity identification and dynamic information borrowing

Synthetic control of a fitness tradeoff in yeast nitrogen metabolism

Background: Microbial communities are involved in many processes relevant to industrial and medical biotechnology, such as the formation of biofilms, lignocellulosic degradation, and hydrogen production. The manipulation of synthetic and natural microbial communities and their underlying ecological parameters, such as fitness, evolvability, and variation, is an increasingly important area of research for synthetic biology. Results: Here, we explored how synthetic control of an endogenous circuit can be used to regulate a tradeoff between fitness in resource abundant and resource limited environments in a population of Saccharomyces cerevisiae. We found that noise in the expression of a key enzyme in ammonia assimilation, Gdh1p, mediated a tradeoff between growth in low nitrogen environments and stress resistance in high ammonia environments. We implemented synthetic control of an endogenous Gdh1p regulatory network to construct an engineered strain in which the fitness of the population was tunable in response to an exogenously-added small molecule across a range of ammonia environments. Conclusion: The ability to tune fitness and biological tradeoffs will be important components of future efforts to engineer microbial communities

The Kaon B-parameter in Mixed Action Chiral Perturbation Theory

We calculate the kaon B-parameter, B_K, in chiral perturbation theory for a partially quenched, mixed action theory with Ginsparg-Wilson valence quarks and staggered sea quarks. We find that the resulting expression is similar to that in the continuum, and in fact has only two additional unknown parameters. At one-loop order, taste-symmetry violations in the staggered sea sector only contribute to flavor-disconnected diagrams by generating an O(a^2) shift to the masses of taste-singlet sea-sea mesons. Lattice discretization errors also give rise to an analytic term which shifts the tree-level value of B_K by an amount of O(a^2). This term, however, is not strictly due to taste-breaking, and is therefore also present in the expression for B_K for pure G-W lattice fermions. We also present a numerical study of the mixed B_K expression in order to demonstrate that both discretization errors and finite volume effects are small and under control on the MILC improved staggered lattices.Comment: 29 pages, 4 figures; Expanded spurion discussion, other discussions clarified, version to appear in PR

Danny’s Recumbent Bike Accessibility Device Final Design Report

The purpose of this document is to fully define our design solution and explain our manufacturing and testing results. Our project’s goal is to find a way to allow Danny Knutson, a retired Navy pilot and incomplete quadriplegic with limited use of his arms and an impaired sense of balance, to enter and exit his recumbent tricycle without any discomfort for him or his aide. We completed multiple interviews with Danny, patent research, existing product research, and other technical literature research in order to fully understand the problem. We synthesized this information to create a concrete list of customer wants and needs, which led to a full list of specifications that were developed using the Quality Function Deployment technique. Key specifications from this list that our design will satisfy are as follows, but not limited to: the machine’s range of motion both horizontally and vertically, level of comfortability to use, and force required by the user to operate. These specifications were accepted by our sponsor and we then began the ideation phase of the project. Once we had numerous concepts, we employed the use of a decision matrix to determine the best idea for our project. We then performed preliminary analyses, risk analysis, and cost analysis in order to further develop our concept. After completing further engineering analyses, we refined our design to meet the required specifications. We purchased all necessary components, designed the parts that must be manufactured in-house, and drew up a plan to modify ordered parts for assembly. After all parts were received and manufacturing was complete, we enacted a testing plan on the assembled device. With the device finalized, we traveled to Danny’s home in Sacramento to install the device and complete our final testing. This document details this process and the results of the projec

The HIV Genomic Incidence Assay Meets False Recency Rate and Mean Duration of Recency Infection Performance Standards.

HIV incidence is a primary metric for epidemic surveillance and prevention efficacy assessment. HIV incidence assay performance is evaluated via false recency rate (FRR) and mean duration of recent infection (MDRI). We conducted a meta-analysis of 438 incident and 305 chronic specimens' HIV envelope genes from a diverse global cohort. The genome similarity index (GSI) accurately characterized infection stage across diverse host and viral factors. All except one chronic specimen had GSIs below 0.67, yielding a FRR of 0.33 [0-0.98] %. We modeled the incidence assay biomarker dynamics with a logistic link function assuming individual variabilities in a Beta distribution. The GSI probability density function peaked close to 1 in early infection and 0 around two years post infection, yielding MDRI of 420 [361, 467] days. We tested the assay by newly sequencing 744 envelope genes from 59 specimens of 21 subjects who followed from HIV negative status. Both standardized residuals and Anderson-Darling tests showed that the test dataset was statistically consistent with the model biomarker dynamics. This is the first reported incidence assay meeting the optimal FRR and MDRI performance standards. Signatures of HIV gene diversification can allow precise cross-sectional surveillance with a desirable temporal range of incidence detection

Precessing Jet and Large Dust Grains in the V380 Ori NE Star-forming Region

The V380 Ori NE bipolar outflow was imaged in the SiO and CO J = 1 - 0 lines, and dense cores in L1641 were observed in the 2.0-0.89 mm continuum. The highly collimated SiO jet shows point-symmetric oscillation patterns in both position and velocity, which suggests that the jet axis is precessing and the driving source may belong to a non-coplanar binary system. By considering the position and velocity variabilities together, accurate jet parameters were derived. The protostellar system is viewed nearly edge-on, and the jet has a flow speed of 35 km/s and a precession period of 1600 years. The CO outflow length gives a dynamical timescale of 6300 years, and the protostar must be extremely young. The inferred binary separation of 6-70 au implies that this protobinary system may have been formed through the disk instability process. The continuum spectra of L1641 dense cores indicate that the emission comes from dust, and the fits with modified blackbody functions give emissivity power indices of beta = 0.3-2.2. The emissivity index shows a positive correlation with the molecular line width, but no strong correlation with bolometric luminosity or temperature. V380 Ori NE has a particularly low value of beta = 0.3, which tentatively suggests the presence of millimeter-sized dust grains. Because the dust growth takes millions of years, much longer than the protostellar age, this core may have produced large grains in the starless core stage. HH 34 MMS and HH 147 MMS also have low emissivity indices.Comment: To appear in the Astrophysical Journal Supplement Serie

Valid \u3cem\u3et\u3c/em\u3e-Ratio Inference for IV

In the single-IV model, researchers commonly rely on t-ratio-based inference, even though the literature has quantified its potentially severe large-sample distortions. Building on Stock and Yogo (2005), we introduce the tF critical value function, leading to a standard error adjustment that is a smooth function of the first-stage F-statistic. For one-quarter of specifications in 61 AER papers, corrected standard errors are at least 49 and 136 percent larger than conventional 2SLS standard errors at the 5 percent and 1 percent significance levels, respectively. tF confidence intervals have shorter expected length than those of Anderson and Rubin (1949), whenever both are bounded