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Both mathematical models and biological model systems stand as tractable representations of complex biological systems or behaviors. They facilitate research and provide insights, and they can describe general rules. Models that represent biological processes or formalize general hypotheses are essential to any broad understanding. Mathematical or biological models necessarily omit details of the natural systems and thus may ultimately be "incorrect" representations. A key challenge is that tractability requires relatively simple models but simplification can result in models that are incorrect in their qualitative, broad implications if the abstracted details matter. Our paper discusses this tension, and how we can improve our inferences from models. We advocate for further efforts dedicated to model development, improvement, and acceptance by the scientific community, all of which may necessitate a more explicit discussion of the purpose and power of models. We argue that models should play a central role in reintegrating biology as a way to test our integrated understanding of how molecules, cells, organs, organisms, populations, and ecosystems function. [ABSTRACT FROM AUTHOR]

Motivation: Biological networks are composed of molecular components and their interactions represented by nodes and edges, respectively, in a graph model. Based on this model, there were many studies with respect to effects of node-based mutations on the network dynamics, whereas little attention was paid to edgetic mutations so far. Results: In this paper, we defined an edgetic sensitivity measure that quantifies how likely a converging attractor is changed by edge-removal mutations in a Boolean network model. Through extensive simulations based on that measure, we found interesting properties of highly sensitive edges in both random and real signaling networks. First, the sensitive edges in random networks tend to link two end nodes both of which are susceptible to node-knockout mutations. Interestingly, it was analogous to an observation that the sensitive edges in human signaling networks are likely to connect drug-target genes. We further observed that the edgetic sensitivity predicted drug-targets better than the node-based sensitivity. In addition, the sensitive edges showed distinguished structural characteristics such as a lower connectivity, more involving feedback loops and a higher betweenness. Moreover, their gene-ontology enrichments were clearly different from the other edges. We also observed that genes incident to the highly sensitive interactions are more central by forming a considerably large connected component in human signaling networks. Finally, we validated our approach by showing that most sensitive interactions are promising edgetic drug-targets in p53 cancer and T-cell apoptosis networks. Taken together, the edgetic sensitivity is valuable to understand the complex dynamics of signaling networks. [ABSTRACT FROM AUTHOR]

An important use of measurement error models is to correct regression models for bias due to covariate measurement error. Most measurement error models assume that the observed error-prone covariate (WW ) is a linear function of the unobserved true covariate (X) plus other covariates (Z) in the regression model. In this paper, we consider models for W that include interactions between X and Z. We derive the conditional distribution of X given W and Z and use it to extend the method of regression calibration to this class of measurement error models. We apply the model to dietary data and test whether self-reported dietary intake includes an interaction between true intake and body mass index. We also perform simulations to compare the model to simpler approximate calibration models. [ABSTRACT FROM AUTHOR]

This paper is motivated by a phase I-II clinical trial of a targeted agent for advanced solid tumors. We study a stylized version of this trial with the goal to determine optimal actions in each of two cycles of therapy. A design is presented that generalizes the decision-theoretic two-cycle design of Lee and others (2015. Bayesian dose-finding in two treatment cycles based on the joint utility of efficacy and toxicity. Journal of the American Statistical Association, to appear) to accommodate ordinal outcomes. Backward induction is used to jointly optimize the actions taken for each patient in each of the two cycles, with the second action accounting for the patient's cycle 1 dose and outcomes. A simulation study shows that simpler designs obtained by dichotomizing the ordinal outcomes either perform very similarly to the proposed design, or have much worse performance in some scenarios. We also compare the proposed design with the simpler approaches of optimizing the doses in each cycle separately, or ignoring the distinction between cycles 1 and 2. [ABSTRACT FROM AUTHOR]

In the genomic era, group association tests are of great interest. Due to the overwhelming number of individual genomic features, the power of testing for association of a single genomic feature at a time is often very small, as are the effect sizes for most features. Many methods have been proposed to test association of a trait with a group of features within a functional unit as a whole, e.g. all SNPs in a gene, yet few of these methods account for the fact that generally a substantial proportion of the features are not associated with the trait. In this paper, we propose to model the association for each feature in the group as a mixture of features with no association and features with non-zero associations to explicitly account for the possibility that a fraction of features may not be associated with the trait while other features in the group are. The feature-level associations are first estimated by generalized linear models; the sequence of these estimated associations is then modeled by a hidden Markov chain. To test for global association, we develop a modified likelihood ratio test based on a log-likelihood function that ignores higher order dependency plus a penalty term. We derive the asymptotic distribution of the likelihood ratio test under the null hypothesis. Furthermore, we obtain the posterior probability of association for each feature, which provides evidence of feature-level association and is useful for potential follow-up studies. In simulations and data application, we show that our proposed method performs well when compared with existing group association tests especially when there are only few features associated with the outcome. [ABSTRACT FROM AUTHOR]