Markov Network Structure Learning via Ensemble-of-Forests Models

Real world systems typically feature a variety of different dependency types and topologies that complicate model selection for probabilistic graphical models. We introduce the ensemble-of-forests model, a generalization of the ensemble-of-trees model. Our model enables structure learning of Markov random fields (MRF) with multiple connected components and arbitrary potentials. We present two approximate inference techniques for this model and demonstrate their performance on synthetic data. Our results suggest that the ensemble-of-forests approach can accurately recover sparse, possibly disconnected MRF topologies, even in presence of non-Gaussian dependencies and/or low sample size. We applied the ensemble-of-forests model to learn the structure of perturbed signaling networks of immune cells and found that these frequently exhibit non-Gaussian dependencies with disconnected MRF topologies. In summary, we expect that the ensemble-of-forests model will enable MRF structure learning in other high dimensional real world settings that are governed by non-trivial dependencies.Comment: 13 pages, 6 figure

Similarities and Differences of Blood N-Glycoproteins in Five Solid Carcinomas at Localized Clinical Stage Analyzed by SWATH-MS.

Cancer is mostly incurable when diagnosed at a metastatic stage, making its early detection via blood proteins of immense clinical interest. Proteomic changes in tumor tissue may lead to changes detectable in the protein composition of circulating blood plasma. Using a proteomic workflow combining N-glycosite enrichment and SWATH mass spectrometry, we generate a data resource of 284 blood samples derived from patients with different types of localized-stage carcinomas and from matched controls. We observe whether the changes in the patient's plasma are specific to a particular carcinoma or represent a generic signature of proteins modified uniformly in a common, systemic response to many cancers. A quantitative comparison of the resulting N-glycosite profiles discovers that proteins related to blood platelets are common to several cancers (e.g., THBS1), whereas others are highly cancer-type specific. Available proteomics data, including a SWATH library to study N-glycoproteins, will facilitate follow-up biomarker research into early cancer detection

Sensitive detection of rare disease-Associated cell subsets via representation learning

Rare cell populations play a pivotal role in the initiation and progression of diseases such as cancer. However, the identification of such subpopulations remains a difficult task. This work describes CellCnn, a representation learning approach to detect rare cell subsets associated with disease using high-dimensional single-cell measurements. Using CellCnn, we identify paracrine signalling-, AIDS onset- and rare CMV infection-associated cell subsets in peripheral blood, and extremely rare leukaemic blast populations in minimal residual disease-like situations with frequencies as low as 0.01%.ISSN:2041-172

Automated random model-based testing of stateful systems

72 σ.To PropEr είναι ένα εργαλείο ανοιχτού λογισμικού για τον αυτόματο τυχαίο έλεγχο ιδιοτήτων συναρτήσεων, γραμμένων στη γλώσσα Erlang, από τις προδιαγραφές τους. Αρχικά ήταν επικεντρωμένο στον έλεγχο αγνών συναρτήσεων. Ωστόσο, οι εφαρμογές που υλοποιούνται σε Erlang συνήθως αποτελούνται από κώδικα με εσωτερική κατάσταση. Στην παρούσα διπλωματική εργασία, έχουμε επεκτείνει το PropEr με δύο βιβλιοθήκες που υποστηρίζουν τον τυχαίο ελέγχο συστημάτων με εσωτερική κατάσταση βάσει μοντέλου. Ο χρήστης καλείται να προσδιορίσει ένα μοντέλο της συμπεριφοράς του συστήματος υπό έλεγχο. Δεδομένου αυτού του μοντέλου, ελέγχουμε ένα σύστημα παράγοντας και εκτελώντας ακολουθίες κλήσεων προς αυτό, ενώ καταγράφουμε τις αποκρίσεις του ώστε να επιβεβαιώσουμε ότι το σύστημα παρουσιάζει την αναμενόμενη συμπεριφορά. Η πρώτη βιβλιοθήκη, που ονομάζεται proper\_statem, έχει σχεδιαστεί για τον έλεγχο γενικευ- μένων εξυπηρετητών και άλλων συστημάτων των οποίων η διεπαφή παρουσιάζει εσωτερική κατάσταση. Οι παρενέργειες των συστημάτων προσδιορίζονται μέσω μίας αφηρημένης μηχανής κατάστασης. Η ίδια μηχανή κατάστασης μπορεί επίσης να χρησιμοποιηθεί για την παραγωγή ακολουθιών κλήσεων, οι οποίες θα εκτελεστούν παράλληλα για τον εντοπισμό συνθηκών ανταγωνισμού. Η δεύτερη βιβλιοθήκη, που ονομάζεται proper\_fsm, προσφέρεται για τον έλεγχο συστημάτων που παρουσιάζουν συμπεριφορά μηχανής πεπερασμένης κατάστασης, αφού είναι σχεδιασμένη ώστε να φέρνει την περιγραφή του μοντέλου του συστήματος πολύ κοντά σε ένα διάγραμμα κατάστασης. Ο προσδιορισμός ενός μοντέλου για το σύστημα υπό έλεγχο δεν είναι σε καμία περίπτωση τετριμμένη διαδικασία. Γι'αυτό το λόγο, παρουσιάζουμε λεπτομερή επεξηγηματικά παραδείγματα σχετικά με την αποτελεσματική χρήση των νέων βιβλιοθηκών για τον έλεγχο συστημάτων με εσωτερική κατάσταση.PropEr is an open-source tool for automated random testing of Erlang function properties from specifications. Its original focus was on testing pure functions. Nevertheless, projects implemented in Erlang typically consist of stateful code. In this thesis, we have extended PropEr with two library modules that support random model-based testing of stateful reactive systems. The model behaviour of the system under test should be defined in a callback module. Given this model, we test a stateful system by generating and performing sequences of calls to that system, while monitoring its actual responses to ensure the system behaves as expected. The first module, proper\_statem, is designed to test generic servers and other systems with stateful interfaces, whose side-effects are specified via an abstract state machine. The same state machine specification can also be used for generating sequences of calls that will be executed in parallel to test for race conditions. The second module, proper\_fsm, offers a convenient way to test systems exhibiting a finite state machine behaviour, as it is designed to bring the callback module specification very close to a state diagram. Defining a model of the system under test is by no means a trivial task. To compensate for that, we present detailed tutorials on effectively using the new library modules to test stateful systems.Ειρήνη Π. Αρβανίτ

Altered DNA methylation pattern characterizes the peripheral immune cells of patients with autoimmune hepatitis

International audienceBackground and aims: Little is known about the impact of DNA methylation modifications on autoimmune hepatitis (AIH) pathogenesis and therapeutic response. We investigated the potential alterations of DNA methylation in AIH peripheral lymphocytes at diagnosis and remission.Methods: 10 AIH patients at diagnosis (time-point 1; AIH-tp1), 8/10 following biochemical response (time-point 2; AIH-tp2), 9 primary biliary cholangitis (PBC) and 10 healthy controls (HC) were investigated. Peripheral CD19(+)- and CD4(+)-cells were isolated.Global DNA methylation (5m C)/hydroxymethylation (5hm C) was studied by ELISAs. mRNA of DNA methylation (DNMT1/3A/3B) and their counteracting hydroxymethylation enzymes (TET1/2/3) was determined by quantitative RT-PCR. Epigenome wide association study (EWAS) was performed in CD4(+)-cells (Illumina HumanMethylation 850K array) in AIH and HC. Total 5m C/5hm C was also assessed by immunohistochemistry (IHC) on paraffin embedded liver sections.Results: Reduced TET1 and increased DNMT3A mRNA levels characterized CD19(+) and CD4(+)-lymphocytes from AIH-tp1 compared to HC and PBC respectively, without affecting global DNA 5m C/5hm C. In AIH-tp1, CD4(+) DNMT3A expression was negatively correlated with serum IgG (p=0.03). In remission, DNMT3A decreased in both CD19(+) and CD4(+)-cells compared to AIH-tp1 (p=0.02, p=0.03, respectively). EWAS in CD4(+)-cells from AIH patients confirmed important modifications in genes implicated in immune responses (HLA-DP, TNF, lnRNAs and CD86). IHC showed increased 5hm C staining of periportal infiltrating lymphocytes in AIH-tp1 compared to HC and PBC.Conclusion: Altered TET1 and DNMT3A expressions, characterize peripheral lymphocytes in AIH. DNMT3A was associated with disease activity and decreased following remission. Gene DNA methylation modifications affect immunologic pathways that may play an important role in AIH pathogenesis

Long-term results of mycophenolate mofetil vs. azathioprine use in individuals with autoimmune hepatitis

Background & Aims: We have shown previously that mycophenolate mofetil (MMF) might be used as first-line treatment instead of azathioprine (AZA) in individuals with autoimmune hepatitis (AIH). Herein, we present our long-term prospective data on response and outcome after first-line therapy with MMF in treatment-naïve individuals with AIH, as similar data are missing. Methods: During the 21 years of the study, 292 individuals with AIH were included (females: 213; median age: 59 [17–85] years). Patients received either prednisolone 0.5–1 mg/kg/day alone (n = 19) or in combination with AZA 1–2 mg/kg/day (n = 64) or MMF (n = 183). The tapering schedule of prednisolone was identical between groups. We assessed the rates of complete biochemical response (CBR) at 6 months, 12 months, and the end of follow-up; non-response (4 weeks of treatment); CBR off prednisolone; adverse effects; CBR off treatment; histological remission; and overall and liver-related mortality between the AZA and MMF groups. Results: The MMF group had lower non-response (p = 0.02) and higher CBR rates at 12 months (86 vs. 71.8%; p 60 years, and longer disease duration were independent predictors of liver-related mortality. Conclusions: MMF seems an efficient alternative first-line treatment option for AIH, bearing lower non-response at 4 weeks and higher CBR rates at 12 months and the end of follow-up than AZA. In addition, MMF was proven to be safe, leading more frequently to the eligibility for stopping immunosuppression according to the guidelines. Impact and implications: For more than 40 years, azathioprine (AZA) has been considered the standard treatment for induction and maintenance of response in autoimmune hepatitis (AIH). However, treatment usually needs to be maintained for life, as relapses are common after AZA cessation. Therefore, alternative treatment options are needed. Herein, we showed that the use of mycophenolate mofetil (MMF) as an alternative first-line immunosuppressant was much more efficient in the long-term than AZA as attested by the lower non-response rates at 4 weeks and higher response rates at 12 months and the end of follow-up. Moreover, AZA-treated patients were more prone to change treatment because of intolerance, whereas MMF-treated patients were more often eligible to achieve treatment withdrawal