Testing small study effects in multivariate meta-analysis

Small study effects occur when smaller studies show different, often larger, treatment effects than large ones, which may threaten the validity of systematic reviews and meta-analyses. The most well-known reasons for small study effects include publication bias, outcome reporting bias, and clinical heterogeneity. Methods to account for small study effects in univariate meta-analysis have been extensively studied. However, detecting small study effects in a multivariate meta-analysis setting remains an untouched research area. One of the complications is that different types of selection processes can be involved in the reporting of multivariate outcomes. For example, some studies may be completely unpublished while others may selectively report multiple outcomes. In this paper, we propose a score test as an overall test of small study effects in multivariate meta-analysis. Two detailed case studies are given to demonstrate the advantage of the proposed test over various naive applications of univariate tests in practice. Through simulation studies, the proposed test is found to retain nominal Type I error rates with considerable power in moderate sample size settings. Finally, we also evaluate the concordance between the proposed tests with the naive application of univariate tests by evaluating 44 systematic reviews with multiple outcomes from the Cochrane Database.     

Adjoint systems for models of cell signaling pathways and their application to parameter fitting

The paper concerns the problem of fitting mathematical models of cell signaling pathways. Such models frequently take the form of sets of nonlinear ordinary differential equations. While the model is continuous in time, the performance index used in the fitting procedure involves measurements taken at discrete time moments. Adjoint sensitivity analysis is a tool which can be used for finding the gradient of a performance index in the space of parameters of the model. In the paper, a structural formulation of adjoint sensitivity analysis called the generalized backpropagation through time (GBPTT) is used. The method is especially suited for hybrid, continuous-discrete time systems. As an example, we use the mathematical model NF-kappaB of the regulatory module, which plays a major role in the innate immune response in animals.     

Morphing the hyomandibular skeleton in development and evolution

How might changes in developmental regulatory pathways underlie evolutionary changes in morphology? Here we focus on a particular pathway regulated by a secreted, signaling peptide, Endothelin1 (Edn1). Developmental genetic analyses show the Edn1-pathway to be crucial for hyomandibular patterning, and we discuss our work with zebrafish suggesting how the signal may function in regulating numbers of skeletal elements, their sizes and their shapes. We then review a broader collection of comparative studies that examine morphological evolution of a subset of the same skeletal elements-the opercular-branchiostegal series of bones of the hyoid arch. We find that phenotypic changes in zebrafish mutants copy evolutionary changes that recur along many actinopterygian lineages. Hence the developmental genetic studies are informative for providing candidate pathways for macroevolution of facial morphology, as well as for our understanding of how these pathways work.     

Functional studies on native and mutated forms of perilipins. A role in protein kinase A-mediated lipolysis of triacylglycerols

Perilipin A coats the lipid storage droplets in adipocytes and is polyphosphorylated by protein kinase A (PKA); the fact that PKA activates lipolysis in adipocytes suggests a role for perilipins in this process. To assess whether perilipins participate directly in PKA-mediated lipolysis, we have expressed constructs coding for native and mutated forms of the two major splice variants of the perilipin gene, perilipins A and B, in Chinese hamster ovary fibroblasts. Perilipins localize to lipid droplet surfaces and displace the adipose differentiation-related protein that normally coats the droplets in these cells. Perilipin A inhibits triacylglycerol hydrolysis by 87% when PKA is quiescent, but activation of PKA and phosphorylation of perilipin A engenders a 7-fold lipolytic activation. Mutation of PKA sites within the N-terminal region of perilipin abrogates the PKA-mediated lipolytic response. In contrast, perilipin B exerts only minimal protection against lipolysis and is unresponsive to PKA activation. Since Chinese hamster ovary cells contain no PKA-activated lipase, we conclude that the expression of perilipin A alone is sufficient to confer PKA-mediated lipolysis in these cells. Moreover, the data indicate that the unique C-terminal portion of perilipin A is responsible for its protection against lipolysis and that phosphorylation at the N-terminal PKA sites attenuates this protective effect.