Maximum Likelihood Estimation in Gaussian Chain Graph Models under the Alternative Markov Property

The AMP Markov property is a recently proposed alternative Markov property for chain graphs. In the case of continuous variables with a joint multivariate Gaussian distribution, it is the AMP rather than the earlier introduced LWF Markov property that is coherent with data-generation by natural block-recursive regressions. In this paper, we show that maximum likelihood estimates in Gaussian AMP chain graph models can be obtained by combining generalized least squares and iterative proportional fitting to an iterative algorithm. In an appendix, we give useful convergence results for iterative partial maximization algorithms that apply in particular to the described algorithm.Comment: 15 pages, article will appear in Scandinavian Journal of Statistic

Comprehensive comparison of in silico MS/MS fragmentation tools of the CASMI contest: database boosting is needed to achieve 93% accuracy.

In mass spectrometry-based untargeted metabolomics, rarely more than 30% of the compounds are identified. Without the true identity of these molecules it is impossible to draw conclusions about the biological mechanisms, pathway relationships and provenance of compounds. The only way at present to address this discrepancy is to use in silico fragmentation software to identify unknown compounds by comparing and ranking theoretical MS/MS fragmentations from target structures to experimental tandem mass spectra (MS/MS). We compared the performance of four publicly available in silico fragmentation algorithms (MetFragCL, CFM-ID, MAGMa+ and MS-FINDER) that participated in the 2016 CASMI challenge. We found that optimizing the use of metadata, weighting factors and the manner of combining different tools eventually defined the ultimate outcomes of each method. We comprehensively analysed how outcomes of different tools could be combined and reached a final success rate of 93% for the training data, and 87% for the challenge data, using a combination of MAGMa+, CFM-ID and compound importance information along with MS/MS matching. Matching MS/MS spectra against the MS/MS libraries without using any in silico tool yielded 60% correct hits, showing that the use of in silico methods is still important

Mutation of ornithine transcarbamylase (H136R) in a girl with severe intermittent orotic aciduria but normal enzyme activity

Ornithine transcarbamylase deficiency shows X-linked inheritance with partial dominant expression in carrier females. We studied a girl with intermittent severe orotic aciduria and mild hyperammonaemia despite apparently normal enzyme activity in the liver. Sequence analysis of all 10 exons of the ornithine transcarbamylase gene revealed a novel a → G exchange (A502G) in exon 5 which changes His-136 to arginine in the ornithine transcarbamylase protein. Km values for carbamyl phosphate and ornithine determined in the patient's liver were comparable to those of wild-type enzyme but, unlike the wild-type enzyme, the mutant enzyme was unstable upon freezing and thawing. Electron microscopy revealed several giant mitochondria with paracrystalline inclusions. The results are compatible with the assumption that the mutant enzyme cannot form a functional complex with carbamyl phosphate synthetase and the ornithine carrier, resulting in decreased availability of substrates and diminished enzyme activity in viv

Discovering a junction tree behind a Markov network by a greedy algorithm

In an earlier paper we introduced a special kind of k-width junction tree, called k-th order t-cherry junction tree in order to approximate a joint probability distribution. The approximation is the best if the Kullback-Leibler divergence between the true joint probability distribution and the approximating one is minimal. Finding the best approximating k-width junction tree is NP-complete if k>2. In our earlier paper we also proved that the best approximating k-width junction tree can be embedded into a k-th order t-cherry junction tree. We introduce a greedy algorithm resulting very good approximations in reasonable computing time. In this paper we prove that if the Markov network underlying fullfills some requirements then our greedy algorithm is able to find the true probability distribution or its best approximation in the family of the k-th order t-cherry tree probability distributions. Our algorithm uses just the k-th order marginal probability distributions as input. We compare the results of the greedy algorithm proposed in this paper with the greedy algorithm proposed by Malvestuto in 1991.Comment: The paper was presented at VOCAL 2010 in Veszprem, Hungar

Pitfalls of using the risk ratio in meta‐analysis

For meta-analysis of studies that report outcomes as binomial proportions, the most popular measure of effect is the odds ratio (OR), usually analyzed as log(OR). Many meta-analyses use the risk ratio (RR) and its logarithm, because of its simpler interpretation. Although log(OR) and log(RR) are both unbounded, use of log(RR) must ensure that estimates are compatible with study-level event rates in the interval (0, 1). These complications pose a particular challenge for random-effects models, both in applications and in generating data for simulations. As background we review the conventional random-effects model and then binomial generalized linear mixed models (GLMMs) with the logit link function, which do not have these complications. We then focus on log-binomial models and explore implications of using them; theoretical calculations and simulation show evidence of biases. The main competitors to the binomial GLMMs use the beta-binomial (BB) distribution, either in BB regression or by maximizing a BB likelihood; a simulation produces mixed results. Two examples and an examination of Cochrane meta-analyses that used RR suggest bias in the results from the conventional inverse-variance-weighted approach. Finally, we comment on other measures of effect that have range restrictions, including risk difference, and outline further research

Total Positivity in Markov Structures

We discuss properties of distributions that are multivariate totally positive of order two (MTP$_{2}$) related to conditional independence. In particular, we show that any independence model generated by an MTP$_{2}$ distribution is a compositional semigraphoid which is upward-stable and singleton-transitive. In addition, we prove that any MTP$_{2}$ distribution satisfying an appropriate support condition is faithful to its concentration graph. Finally, we analyze factorization properties of MTP$_{2}$ distributions and discuss ways of constructing MTP$_{2}$ distributions; in particular we give conditions on the log-linear parameters of a discrete distribution which ensure MTP$_{2}$ and characterize conditional Gaussian distributions which satisfy MTP$_{2}$.SF was supported in part by an NSERC Discovery Research Grant, KS by grant #FA9550-12-1-0392 from the U.S. Air Force Office of Scientic Research (AFOSR) and the Defense Advanced Research Projects Agency (DARPA), CU by the Austrian Science Fund (FWF) Y 903-N35, and PZ by the European Union Seventh Framework Programme PIOF-GA-2011-300975

Qualitative evaluation of a preventive intervention for the offspring of parents with a history of depression

Background: Meta-analyses of randomised controlled trials suggest that psychological interventions to reduce children’s risk of depression are effective. Nevertheless, these effects are modest and diminish over time. The Medical Research Council recommends a mixed-methods approach to the evaluation of complex interventions. By gaining a more thorough understanding of participants’ perspectives, qualitative evaluations of preventive interventions could improve their efficacy, longevity and transfer into clinical practice. Methods: 18 parents and 22 children who had received a 12-session family- and group-based cognitivebehavioural intervention to prevent youth depression as part of a randomised controlled trial took part in semistructured interviews or a focus group about aspects which had been perceived as helpful, elements they were still using after the intervention had ended, and suggestions they had for improving the intervention. Results: The chance to openly share and discuss their experiences of depression within and between families was considered helpful by both children and parents. Children benefitted the most from learning coping strategies for dealing with stress and many still used them in everyday life. Parents profited mostly from increasing positive family time, but noted that maintaining new routines after the end of the intervention proved difficult. Participants were generally content with the intervention but commented on how tiring and time consuming it was. Conclusions: Managing parents’ expectations of family-based interventions in terms of their own mental health needs (versus those of their children) and leaving more room for open discussions may result in interventions which are more appealing to participating families. Increasing intervals between sessions may be one means of improving the longevity of interventions. Trial registration: The original RCT this evaluation is a part of was registered under NCT02115880

Carbonyl reductase as a significant predictor of survival and lymph node metastasis in epithelial ovarian cancer

We have recently reported a novel function for carbonyl reductase (CR), namely, its ability to modulate the metastatic potential of malignant mouse cells. Because there are currently no data addressing a similar function for CR in human cancers, the aim of this study was to assess a correlation between survival and metastasis, and CR level in epithelial ovarian cancer. Using anti-CR antibody, immunohistochemical staining was performed on 73 epithelial ovarian cancers, 13 borderline malignant tumours, and 25 benign ovarian tumours for a total of 111 specimens. The combined rate for strongly and weakly positive reactions for CR was 32.0% for benign tumours, 38.5% for borderline malignant tumours, and 61.6% for ovarian cancers. The CR-positive rate was 35.7% (weakly positive alone) for ovarian cancers with retroperitoneal lymph node (RLN) metastasis and 67.8% for those without RLN metastasis (P< 0.05). The 5-year survival rate was 62.7% for the patients with CR-negative cancer and 86.1% for those with CR-positive cancer (P< 0.05). The present results indicate that decreased CR expression in epithelial ovarian cancer is associated with RLN metastasis and poor survival.© 2001 Cancer Research Campaignhttp://www.bjcancer.co

Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia

Copyright @ 2013 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. There is a correlation between expansion length, the amount of residual frataxin and the severity of disease. As the coding sequence is unaltered, pharmacological up-regulation of FXN expression may restore frataxin to therapeutic levels. To facilitate screening of compounds that modulate FXN expression in a physiologically relevant manner, we established a cellular genomic reporter assay consisting of a stable human cell line containing an FXN-EGFP fusion construct, in which the EGFP gene is fused in-frame with the entire normal human FXN gene present on a BAC clone. The cell line was used to establish a fluorometric cellular assay for use in high throughput screening (HTS) procedures. A small chemical library containing FDA-approved compounds and natural extracts was screened and analyzed. Compound hits identified by HTS were further evaluated by flow cytometry in the cellular genomic reporter assay. The effects on FXN mRNA and frataxin protein levels were measured in lymphoblast and fibroblast cell lines derived from individuals with FRDA and in a humanized GAA repeat expansion mouse model of FRDA. Compounds that were established to increase FXN gene expression and frataxin levels included several anti-cancer agents, the iron-chelator deferiprone and the phytoalexin resveratrol.Muscular Dystrophy Association (USA), the National Health and Medical Research Council (Australia), the Friedreich’s Ataxia Research Alliance (USA), the Brockhoff Foundation (Australia), the Friedreich Ataxia Research Association (Australasia), Seek A Miracle (USA) and the Victorian Government’s Operational Infrastructure Support Program