Non-compartment model to compartment model pharmacokinetics transformation meta-analysis – a multivariate nonlinear mixed model

Background To fulfill the model based drug development, the very first step is usually a model establishment from published literatures. Pharmacokinetics model is the central piece of model based drug development. This paper proposed an important approach to transform published non-compartment model pharmacokinetics (PK) parameters into compartment model PK parameters. This meta-analysis was performed with a multivariate nonlinear mixed model. A conditional first-order linearization approach was developed for statistical estimation and inference. Results Using MDZ as an example, we showed that this approach successfully transformed 6 non-compartment model PK parameters from 10 publications into 5 compartment model PK parameters. In simulation studies, we showed that this multivariate nonlinear mixed model had little relative bias (<1%) in estimating compartment model PK parameters if all non-compartment PK parameters were reported in every study. If there missing non-compartment PK parameters existed in some published literatures, the relative bias of compartment model PK parameter was still small (<3%). The 95% coverage probabilities of these PK parameter estimates were above 85%. Conclusions This non-compartment model PK parameter transformation into compartment model meta-analysis approach possesses valid statistical inference. It can be routinely used for model based drug development

Analysing trajectories of a longitudinal exposure: A causal perspective on common methods in lifecourse research

Longitudinal data is commonly analysed to inform prevention policies for diseases that may develop throughout life. Commonly methods interpret the longitudinal data as a series of discrete measurements or as continuous patterns. Some of the latter methods condition on the outcome, aiming to capture ‘average’ patterns within outcome groups, while others capture individual-level pattern features before relating these to the outcome. Conditioning on the outcome may prevent meaningful interpretation. Repeated measurements of a longitudinal exposure (weight) and later outcome (glycated haemoglobin levels) were simulated to match three scenarios: one with no causal relationship between growth rate and glycated haemoglobin; two with a positive causal effect of growth rate on glycated haemoglobin. Two methods that condition on the outcome and one that did not were applied to the data in 1000 simulations. The interpretation of the two-step method matched the simulation in all causal scenarios, but that of the methods conditioning on the outcome did not. Methods that condition on the outcome do not accurately represent a causal relationship between a longitudinal pattern and outcome. Researchers considering longitudinal data should carefully determine if they wish to analyse longitudinal data as a series of discrete time points or by extracting pattern features

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Comparing chromosomal and mitochondrial phylogenies of the Indriidae (Primates, Lemuriformes)

The Malagasy primate family Indriidae comprises three genera with up to 19 species. Cytogenetic and molecular phylogenies of the Indriidae have been performed with special attention to the genus Propithecus. Comparative R-banding and FISH with human paints were applied to karyotypes of representatives of all three genera and confirmed most of the earlier R-banding results. However, additional chromosomal rearrangements were detected. A reticulated and a cladistic phylogeny, the latter including hemiplasies, have been performed. Cladistic analysis of cytogenetic data resulted in a phylogenetic tree revealing (1) monophyly of the family Indriidae, (2) monophyly of the genus Avahi, (3) sister–group relationships between Propithecus diadema and Propithecus edwardsi, and (4) the grouping of the latter with Indri indri, Propithecus verreauxi, and Propithecus tattersalli, and thus suggesting paraphyly of the genus Propithecus. A molecular phylogeny based on complete mitochondrial cytochrome b sequences of 16 species indicated some identical relationships, such as the monophyly of Avahi and the sister–group relationships of the eastern (P. diadema and P. edwardsi) to the western Propithecus species (P. verreauxi, Propithecus coquereli, and P. tattersalli). However, the main difference between the molecular and cytogenetic phylogenies consists in an early divergence of Indri in the molecular phylogeny while in the chromosomal phylogeny it is nested within Propithecus. The similarities and differences between molecular and cytogenetic phylogenies in relation to data on the species’ geographic distributions and mating systems allow us to propose a scenario of the evolution of Indriidae. Chromosomal and molecular processes alone or in combination created a reproductive barrier that was then followed by further speciation processes

Widespread Over-Expression of the X Chromosome in Sterile F1 Hybrid Mice

The X chromosome often plays a central role in hybrid male sterility between species, but it is unclear if this reflects underlying regulatory incompatibilities. Here we combine phenotypic data with genome-wide expression data to directly associate aberrant expression patterns with hybrid male sterility between two species of mice. We used a reciprocal cross in which F1 males are sterile in one direction and fertile in the other direction, allowing us to associate expression differences with sterility rather than with other hybrid phenotypes. We found evidence of extensive over-expression of the X chromosome during spermatogenesis in sterile but not in fertile F1 hybrid males. Over-expression was most pronounced in genes that are normally expressed after meiosis, consistent with an X chromosome-wide disruption of expression during the later stages of spermatogenesis. This pattern was not a simple consequence of faster evolutionary divergence on the X chromosome, because X-linked expression was highly conserved between the two species. Thus, transcriptional regulation of the X chromosome during spermatogenesis appears particularly sensitive to evolutionary divergence between species. Overall, these data provide evidence for an underlying regulatory basis to reproductive isolation in house mice and underscore the importance of transcriptional regulation of the X chromosome to the evolution of hybrid male sterility