554 research outputs found
Frequentist analysis of basket trials with one-sample Mantel-Haenszel procedures
Recent substantial advances of molecular targeted oncology drug development
is requiring new paradigms for early-phase clinical trial methodologies to
enable us to evaluate efficacy of several subtypes simultaneously and
efficiently. The concept of the basket trial is getting of much attention to
realize this requirement borrowing information across subtypes, which are
called baskets. Bayesian approach is a natural approach to this end and indeed
the majority of the existing proposals relies on it. On the other hand, it
required complicated modeling and may not necessarily control the type 1 error
probabilities at the nominal level. In this paper, we develop a purely
frequentist approach for basket trials based on one-sample Mantel-Haenszel
procedure relying on a very simple idea for borrowing information under the
common treatment effect assumption over baskets. We show that the proposed
estimator is consistent under two limiting models of the large strata and
sparse data limiting models (dually consistent) and propose dually consistent
variance estimators. The proposed Mantel-Haenszel estimators are interpretable
even if the common treatment assumptions are violated. Then, we can design
basket trials in a confirmatory matter. We also propose an information
criterion approach to identify effective subclass of baskets
Determining amino acid requirements from repeated observations on indicator amino acid oxidation method by mixed-effect change-point regression models
In nutrition studies, it is often of primary interest to determine the critical threshold value of some biological quantities. To determine the amino acid requirement, the tracer approach including the indicator amino acid oxidation method is useful for the investigation of human subjects. In this approach, measurements of amino acids other than the test amino acid are often repeatedly carried out with various intakes of the test amino acid. Change-point regression models have often been applied to determine the amino acid requirement. However, within-subject dependence due to repeated measurements has not been sufficiently taken into account. In this paper, we propose a mixed-effect change-point model to estimate the amino acid requirements when utilizing the tracer approach. Inference based on Akaike Information Criteria is introduced to include selection of the optimal model and construction of a confidence interval. Our method can easily be applied with a standard software package, and we found that appropriate accounting for within-subject dependence may lead to a much narrower confidence interval. We recommend application of a mixed-effect change-point regression model to determine the amino acid requirements in studies utilizing the tracer approach
List of Polypores and Other Aphyllophoraceous Fungi Collected in the Lambir Hills National Park, Sarawak, Malaysia
We collected 933 specimens of polypores and other aphyllophoraceous fungi in the Lambir Hills National Park, Sarawak, Malaysia, in 2006. We identified 848 specimens and recorded 57 species and 59 morphospecies. We compare our list to the results of a few former floral studies conducted in and near the park
A simple sensitivity analysis method for unmeasured confounders via linear programming with estimating equation constraints
In estimating the average treatment effect in observational studies, the
influence of confounders should be appropriately addressed. To this end, the
propensity score is widely used. If the propensity scores are known for all the
subjects, bias due to confounders can be adjusted by using the inverse
probability weighting (IPW) by the propensity score. Since the propensity score
is unknown in general, it is usually estimated by the parametric logistic
regression model with unknown parameters estimated by solving the score
equation under the strongly ignorable treatment assignment (SITA) assumption.
Violation of the SITA assumption and/or misspecification of the propensity
score model can cause serious bias in estimating the average treatment effect.
To relax the SITA assumption, the IPW estimator based on the outcome-dependent
propensity score has been successfully introduced. However, it still depends on
the correctly specified parametric model and its identification. In this paper,
we propose a simple sensitivity analysis method for unmeasured confounders. In
the standard practice, the estimating equation is used to estimate the unknown
parameters in the parametric propensity score model. Our idea is to make
inference on the average causal effect by removing restrictive parametric model
assumptions while still utilizing the estimating equation. Using estimating
equations as constraints, which the true propensity scores asymptotically
satisfy, we construct the worst-case bounds for the average treatment effect
with linear programming. Different from the existing sensitivity analysis
methods, we construct the worst-case bounds with minimal assumptions. We
illustrate our proposal by simulation studies and a real-world example.Comment: 16 pages, 5 tables, 2 figure
Molecular and Genetic Interactions between CCN2 and CCN3 behind Their Yin-Yang Collaboration
Cellular communication network factor (CCN) 2 and 3 are the members of the CCN family that conduct the harmonized development of a variety of tissues and organs under interaction with multiple biomolecules in the microenvironment. Despite their striking structural similarities, these two members show contrastive molecular functions as well as temporospatial emergence in living tissues. Typically, CCN2 promotes cell growth, whereas CCN3 restrains it. Where CCN2 is produced, CCN3 disappears. Nevertheless, these two proteins collaborate together to execute their mission in a yin-yang fashion. The apparent functional counteractions of CCN2 and CCN3 can be ascribed to their direct molecular interaction and interference over the cofactors that are shared by the two. Recent studies have revealed the mutual negative regulation systems between CCN2 and CCN3. Moreover, the simultaneous and bidirectional regulatory system of CCN2 and CCN3 is also being clarified. It is of particular note that these regulations were found to be closely associated with glycolysis, a fundamental procedure of energy metabolism. Here, the molecular interplay and metabolic gene regulation that enable the yin-yang collaboration of CCN2 and CCN3 typically found in cartilage development/regeneration and fibrosis are described
Retrotransposons Manipulating Mammalian Skeletal Development in Chondrocytes
Retrotransposons are genetic elements that copy and paste themselves in the host genome through transcription, reverse-transcription, and integration processes. Along with their proliferation in the genome, retrotransposons inevitably modify host genes around the integration sites, and occasionally create novel genes. Even now, a number of retrotransposons are still actively editing our genomes. As such, their profound role in the evolution of mammalian genomes is obvious; thus, their contribution to mammalian skeletal evolution and development is also unquestionable. In mammals, most of the skeletal parts are formed and grown through a process entitled endochondral ossification, in which chondrocytes play central roles. In this review, current knowledge on the evolutional, physiological, and pathological roles of retrotransposons in mammalian chondrocyte differentiation and cartilage development is summarized. The possible biological impact of these mobile genetic elements in the future is also discussed
Novel intracellular effects of human connective tissue growth factor expressed in Cos-7 cells
AbstractTo clarify the multiple functionality of connective tissue growth factor (CTGF), we examined the effects of nascent CTGF within the cell by transient expression. In Cos-7 cells, expression of human CTGF induced an altered cell morphology. It was associated with an increased cellular DNA content and loose attachment, indicating the cells were in G2/M phase. Overexpression of CTGF did not induce cell growth, whereas recombinant CTGF efficiently stimulated the proliferation extracellularly. These results indicate that intracellular CTGF may act as an antimitotic agent, thus it should also be noted that nascent CTGF was found to accumulate around the central mitotic machinery
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