Causal graphical models in systems genetics: A unified framework for joint inference of causal network and genetic architecture for correlated phenotypes

Causal inference approaches in systems genetics exploit quantitative trait loci (QTL) genotypes to infer causal relationships among phenotypes. The genetic architecture of each phenotype may be complex, and poorly estimated genetic architectures may compromise the inference of causal relationships among phenotypes. Existing methods assume QTLs are known or inferred without regard to the phenotype network structure. In this paper we develop a QTL-driven phenotype network method (QTLnet) to jointly infer a causal phenotype network and associated genetic architecture for sets of correlated phenotypes. Randomization of alleles during meiosis and the unidirectional influence of genotype on phenotype allow the inference of QTLs causal to phenotypes. Causal relationships among phenotypes can be inferred using these QTL nodes, enabling us to distinguish among phenotype networks that would otherwise be distribution equivalent. We jointly model phenotypes and QTLs using homogeneous conditional Gaussian regression models, and we derive a graphical criterion for distribution equivalence. We validate the QTLnet approach in a simulation study. Finally, we illustrate with simulated data and a real example how QTLnet can be used to infer both direct and indirect effects of QTLs and phenotypes that co-map to a genomic region.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS288 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Horticultural Applications of a Newly Revised USDA Plant Hardiness Zone Map

The accurate prediction of winter injury caused by low-temperature events is a key component of the effective cultivation of woody and herbaceous perennial plants. A common method employed to visualize geographic patterns in the severity of low-temperature events is to map a climatological variable that closely correlates with plant survival. The U.S. Department of Agriculture Plant Hardiness Zone Map (PHZM) is constructed for that purpose. We present a short history of PHZM development, culminating in the recent production of a new, high-resolution version of the PHZM, and discuss how such maps relate to winterhardiness per se and to other climatic factors that affect hardiness. The new PHZM is based on extreme minimum-temperature data logged annually from 1976 to 2005 at 7983 weather stations in the United States, Puerto Rico, and adjacent regions in Canada and Mexico. The PHZM is accessible via an interactive website, which facilitates a wide range of horticultural applications. For example, we highlight how the PHZM can be used as a tool for site evaluation for vineyards in the Pacific northwestern United States and as a data layer in conjunction with moisture-balance data to predict the survival of Yugoslavian woody plants in South Dakota. In addition, the new map includes a zip code finder, and we describe how it may be used by governmental agencies for risk management and development of recommended plant lists, by horticultural firms to schedule plant shipments, and by other commercial interests that market products seasonally

Genomic Data from NSCLC Tumors Reveals Correlation between SHP-2 Activity and PD-L1 Expression and Suggests Synergy in Combining SHP-2 and PD-1/PD-L1 Inhibitors

The identification of novel therapies, new strategies for combination of therapies, and repurposing of drugs approved for other indications are all important for continued progress in the fight against lung cancers. Antibodies that target immune checkpoints can unmask an immunologically hot tumor from the immune system of a patient. However, despite accounts of significant tumor regression resulting from these medications, most patients do not respond. In this study, we sought to use protein expression and RNA sequencing data from The Cancer Genome Atlas and two smaller studies deposited onto the Gene Expression Omnibus (GEO) to advance our hypothesis that inhibition of SHP-2, a tyrosine phosphatase, will improve the activity of immune checkpoint inhibitors (ICI) that target PD-1 or PD-L1 in lung cancers. We first collected protein expression data from The Cancer Proteome Atlas (TCPA) to study the association of SHP-2 and PD-L1 expression in lung adenocarcinomas. RNA sequencing data was collected from the same subjects through the NCI Genetic Data Commons and evaluated for expression of the PTPN11 (SHP-2) and CD274 (PD-L1) genes. We then analyzed RNA sequencing data from a series of melanoma patients who were either treatment naïve or resistant to ICI therapy. PTPN11 and CD274 expression was compared between groups. Finally, we analyzed gene expression and drug response data collected from 21 non-small cell lung cancer (NSCLC) patients for PTPN11 and CD274 expression. From the three studies, we hypothesize that the activity of SHP-2, rather than the expression, likely controls the expression of PD-L1 as only a weak relationship between PTPN11 and CD274 expression in either lung adenocarcinomas or melanomas was observed. Lastly, the expression of CD274, not PTPN11, correlates with response to ICI in NSCLC

Behavior of the Escape Rate Function in Hyperbolic Dynamical Systems

For a fixed initial reference measure, we study the dependence of the escape rate on the hole for a smooth or piecewise smooth hyperbolic map. First, we prove the existence and Holder continuity of the escape rate for systems with small holes admitting Young towers. Then we consider general holes for Anosov diffeomorphisms, without size or Markovian restrictions. We prove bounds on the upper and lower escape rates using the notion of pressure on the survivor set and show that a variational principle holds under generic conditions. However, we also show that the escape rate function forms a devil's staircase with jumps along sequences of regular holes and present examples to elucidate some of the difficulties involved in formulating a general theory.Comment: 21 pages. v2 differs from v1 only by additions to the acknowledgment

Inflammatory-Induced Hibernation in the Fetus: Priming of Fetal Sheep Metabolism Correlates with Developmental Brain Injury

Prenatal inflammation is considered an important factor contributing to preterm birth and neonatal mortality and morbidity. The impact of prenatal inflammation on fetal bioenergetic status and the correlation of specific metabolites to inflammatory-induced developmental brain injury are unknown. We used a global metabolomics approach to examine plasma metabolites differentially regulated by intrauterine inflammation. Preterm-equivalent sheep fetuses were randomized to i.v. bolus infusion of either saline-vehicle or LPS. Blood samples were collected at baseline 2 h, 6 h and daily up to 10 days for metabolite quantification. Animals were killed at 10 days after LPS injection, and brain injury was assessed by histopathology. We detected both acute and delayed effects of LPS on fetal metabolism, with a long-term down-regulation of fetal energy metabolism. Within the first 3 days after LPS, 121 metabolites were up-regulated or down-regulated. A transient phase (4–6 days), in which metabolite levels recovered to baseline, was followed by a second phase marked by an opposing down-regulation of energy metabolites, increased pO2 and increased markers of inflammation and ADMA. The characteristics of the metabolite response to LPS in these two phases, defined as 2 h to 2 days and at 6–9 days, respectively, were strongly correlated with white and grey matter volumes at 10 days recovery. Based on these results we propose a novel concept of inflammatory-induced hibernation of the fetus. Inflammatory priming of fetal metabolism correlated with measures of brain injury, suggesting potential for future biomarker research and the identification of therapeutic targets

Re-structuring of marine communities exposed to environmental change

Species richness is the most commonly used but controversial biodiversity metric in studies on aspects of community stability such as structural composition or productivity. The apparent ambiguity of theoretical and experimental findings may in part be due to experimental shortcomings and/or heterogeneity of scales and methods in earlier studies. This has led to an urgent call for improved and more realistic experiments. In a series of experiments replicated at a global scale we translocated several hundred marine hard bottom communities to new environments simulating a rapid but moderate environmental change. Subsequently, we measured their rate of compositional change (re-structuring) which in the great majority of cases represented a compositional convergence towards local communities. Re-structuring is driven by mortality of community components (original species) and establishment of new species in the changed environmental context. The rate of this re-structuring was then related to various system properties. We show that availability of free substratum relates negatively while taxon richness relates positively to structural persistence (i.e., no or slow re-structuring). Thus, when faced with environmental change, taxon-rich communities retain their original composition longer than taxon-poor communities. The effect of taxon richness, however, interacts with another aspect of diversity, functional richness. Indeed, taxon richness relates positively to persistence in functionally depauperate communities, but not in functionally diverse communities. The interaction between taxonomic and functional diversity with regard to the behaviour of communities exposed to environmental stress may help understand some of the seemingly contrasting findings of past research

Hippocampal internal architecture and postoperative seizure outcome in temporal lobe epilepsy due to hippocampal sclerosis

AbstractPurposeSemi-quantitative analysis of hippocampal internal architecture (HIA) on MRI has been shown to be a reliable predictor of the side of seizure onset in patients with temporal lobe epilepsy (TLE). In the present study, we investigated the relationship between postoperative seizure outcome and preoperative semi-quantitative measures of HIA.MethodsWe determined HIA on high in-plane resolution preoperative T2 short tau inversion recovery MR images in 79 patients with presumed unilateral mesial TLE (mTLE) due to hippocampal sclerosis (HS) who underwent amygdalohippocampectomy and postoperative follow up. HIA was investigated with respect to postoperative seizure freedom, neuronal density determined from resected hippocampal specimens, and conventionally acquired hippocampal volume.ResultsHIA ratings were significantly related to some neuropathological features of the resected hippocampus (e.g. neuronal density of selective CA regions, Wyler grades), and bilaterally with preoperative hippocampal volume. However, there were no significant differences in HIA ratings of the to-be-resected or contralateral hippocampus between patients rendered seizure free (ILAE 1) compared to those continuing to experience seizures (ILAE 2-5).ConclusionsThis work indicates that semi-quantitative assessment of HIA on high-resolution MRI provides a surrogate marker of underlying histopathology, but cannot prospectively distinguish between patients who will continue to experience postoperative seizures and those who will be rendered seizure free. The predictive power of HIA for postoperative seizure outcome in non-lesional patients with TLE should be explored