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

Pax3:Fkhr interferes with embryonic Pax3 and Pax7 function: implications for alveolar rhabdomyosarcoma cell of origin.

Journal ArticleTo investigate the role of the translocation-associated gene Pax3:Fkhr in alveolar rhabdomyosarcomas, we generated a Cre-mediated conditional knock-in of Pax3:Fkhr into the mouse Pax3 locus. Exploring embryonic tumor cell origins, we replaced a Pax3 allele with Pax3:Fkhr throughout its expression domain, causing dominant-negative effects on Pax3 and paradoxical activation of the Pax3 target gene, c-Met. Ectopic neuroprogenitor cell proliferation also occurs. In contrast, activation later in embryogenesis in cells that express Pax7 results in viable animals with a postnatal growth defect and a moderately decreased Pax7+ muscle satellite cell pool, phenocopying Pax7 deficiency but remarkably not leading to tumors

Measurement of Subcellular CA2+ Redistribution in Cardiac Muscle In Situ: Time Resolved Rapid Freezing and Electron Probe Microanalysis

To directly assess the physiological roles of sarcoplasmic reticulum (SR) and miitochondria (MT), we have utilized energy dispersive electron probe microanalysis (EPMA) on ultrathin freeze-dried cryosections from isolated papillary muscles, rapidly frozen at precise time points of the contractile cycle. Using this approach, we can detect redistribution of subcellular Ca2+ during the cardiac contractile cycle. Changes in Ca2+ of less than 1.0 mmol/kg dry wt can be detected. By determining the variability of the Ca2+ measurements in preliminary experiments, we have also demonstrated that it is possible to optimize experimental design, i.e., to predict the number of animals per treatment group and the number of X-ray spectra per animal that are required in order to detect a specified Ca2+ difference. Quantitative EPMA of rapidly frozen contracting papillary muscle has also allowed us to correlate the Ca2+ content of SR and MT with the contractile state of the muscle. Our results show a decrease of 40% in the amount of Ca2+ stored in the junctional SR during a cardiac muscle twitch, thus providing direct evidence for a role of the SR as a primary site of Ca2+ release. In addition, we have demonstrated dissociation between MT Ca2+ uptake and activation of regulatory enzymes, such as pyruvate dehydrogenase, indicating that MT Ca2+ uptake is not required for activation of MT metabolism

Midwest Evaluation of the Adult Functioning of Former Foster Youth

The Midwest Evaluation of the Adult Functioning of Former Foster Youth (Midwest Study) is a prospective study that has been following a sample of young people from Iowa, Wisconsin, and Illinois as they transition out of foster care into adulthood. It is a collaborative effort involving Chapin Hall at the University of Chicago; Partners for Our Children at the University of Washington, Seattle; the University of Wisconsin Survey Center; and the public child welfare agencies in Illinois, Iowa, and Wisconsin.The Midwest Study provides a comprehensive picture of how foster youth are faring during this transition since the Foster Care Independence Act of 1999 became law. Foster youth in Iowa, Wisconsin, and Illinois were eligible to participate in the study if they had entered care before their 16th birthday, were still in care at age 17, and had been removed from home for reasons other than delinquency. Baseline survey data were collected from 732 study participants when they were 17 or 18 years old. Study participants were re-interviewed at ages 19 (n = 603), 21 (n = 591), and 23 or 24 (n = 602). A fifth wave of survey data will be collected when study participants are 25 or 26 years old.Because many of the questions Midwest Study participants were also asked as part of the National Longitudinal Study of Adolescent Health, it is possible to make comparisons between this sample of former foster youth and a nationally representative sample of young people in the general population. These comparisons indicate that young people who have aged out of foster care are faring poorly as a group relative to their peers across a variety of domains.The Midwest Study also presents a unique opportunity to compare the outcomes of young people from one state (i.e., Illinois) that allows foster youth to remain in care until their 21st birthday to the outcomes of young people from two other states (i.e., Iowa and Wisconsin) in which foster youth generally age out when they are 18 years old. The data suggest that extending foster care until age 21 may be associated with better outcomes, at least in some domains

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

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