Guy Tsafnat

Advances in the calibration of atom probe tomographic reconstruction

Modern wide field-of-view atom probes permit observation of a wide range of crystallographic features that can be used to calibrate the tomographic reconstruction of the analyzed volume. In this study, methodologies to determine values of the geometric parameters involved in the tomographic reconstruction of atom probe data sets are presented and discussed. The influence of the tip to electrode distance and specimen temperature on these parameters is explored. Significantly, their influence is demonstrated to be very limited, indicating a relatively wide regime of experimental parameters space for sound atom probe tomography (APT) experiments. These methods have been used on several specimens and material types, and the results indicate that the reconstruction parameters are specific to each specimen. Finally, it is shown how an accurate calibration of the reconstruction enables improvements to the quality and reliability of the microscopy and microanalysis capabilities of the atom probe.

Systematic review automation technologies.

Systematic reviews, a cornerstone of evidence-based medicine, are not produced quickly enough to support clinical practice. The cost of production, availability of the requisite expertise and timeliness are often quoted as major contributors for the delay. This detailed survey of the state of the art of information systems designed to support or automate individual tasks in the systematic review, and in particular systematic reviews of randomized controlled clinical trials, reveals trends that see the convergence of several parallel research projects.We surveyed literature describing informatics systems that support or automate the processes of systematic review or each of the tasks of the systematic review. Several projects focus on automating, simplifying and/or streamlining specific tasks of the systematic review. Some tasks are already fully automated while others are still largely manual. In this review, we describe each task and the effect that its automation would have on the entire systematic review process, summarize the existing information system support for each task, and highlight where further research is needed for realizing automation for the task. Integration of the systems that automate systematic review tasks may lead to a revised systematic review workflow. We envisage the optimized workflow will lead to system in which each systematic review is described as a computer program that automatically retrieves relevant trials, appraises them, extracts and synthesizes data, evaluates the risk of bias, performs meta-analysis calculations, and produces a report in real time.

The automation of systematic reviews

Would lead to best currently available evidence at the push of a button

System Health and Intrusion Monitoring Using a Hierarchy of Constraints

This paper presents a new approach to run-time security monitoring that can detect system abnormalities including attacks, faults, or operational errors. The approach, System Health and Intrusion Monitoring (SHIM), employs a hierarchy of constraints to describe correct operation of a system at various levels of abstraction. The constraints capture static behavior, dynamic behavior, and time-critical behavior of a system. A system in execution will be monitored for violation of the constraints, which may indicate potential security problems in the system. SHIM is based on specification-based intrusion detection, but it attempts to provide a systematic framework for developing the specifications/ constraints. SHIM does not detect directly the intrusive actions in an attack, but their manifestations as violations of constraints. In this paper, we describe the constraint model and the methodology for developing the constraints. In addition, we present preliminary results on the constraints developed for host programs and network protocols. By bounding the behavior of various system components at different levels of abstraction, SHIM has a high chance of detecting different types of attacks and their variants.

RAC: Repository of Antibiotic resistance Cassettes

Antibiotic resistance in bacteria is often due to acquisition of resistance genes associated with different mobile genetic elements. In Gram-negative bacteria, many resistance genes are found as part of small mobile genetic elements called gene cassettes, generally found integrated into larger elements called integrons. Integrons carrying antibiotic resistance gene cassettes are often associated with mobile elements and here are designated ‘mobile resistance integrons’ (MRIs). More than one cassette can be inserted in the same integron to create arrays that contribute to the spread of multi-resistance. In many sequences in databases such as GenBank, only the genes within cassettes, rather than whole cassettes, are annotated and the same gene/cassette may be given different names in different entries, hampering analysis. We have developed the Repository of Antibiotic resistance Cassettes (RAC) website to provide an archive of gene cassettes that includes alternative gene names from multiple nomenclature systems and allows the community to contribute new cassettes. RAC also offers an additional function that allows users to submit sequences containing cassettes or arrays for annotation using the automatic annotation system Attacca. Attacca recognizes features (gene cassettes, integron regions) and identifies cassette arrays as patterns of features and can also distinguish minor cassette variants that may encode different resistance phenotypes (aacA4 cassettes and bla cassettes-encoding β-lactamases). Gaps in annotations are manually reviewed and those found to correspond to novel cassettes are assigned unique names. While there are other websites dedicated to integrons or antibiotic resistance genes, none includes a complete list of antibiotic resistance gene cassettes in MRI or offers consistent annotation and appropriate naming of all of these cassettes in submitted sequences. RAC thus provides a unique resource for researchers, which should reduce confusion and improve the quality of annotations of gene cassettes in integrons associated with antibiotic resistance. Database URL: http://www2.chi.unsw.edu.au/rac.

Genetic and epigenetic biomarkers of colorectal cancer.

Cancer is a heterogeneous disease caused, in part, by genetic and epigenetic alterations. These changes have been explored in studies of the pathogenesis of colorectal cancer (CRC) and have led to the identification of many biomarkers of disease progression. However, the number of biomarkers that have been incorporated into clinical practice is surprisingly small. We review the genetic and epigenetic mechanisms of colorectal cancer and discuss molecular markers recommended for use in early detection, screening, diagnosis, determination of prognosis, and prediction of treatment outcomes. We also review important areas for future research.

Citation networks of related trials are often disconnected: Implications for bidirectional citation searches

BACKGROUND AND OBJECTIVES Reports of randomized controlled trials (RCTs) should set findings within the context of previous research. The resulting network of citations would also provide an alternative search method for clinicians, researchers, and systematic reviewers seeking to base decisions on all available evidence. We sought to determine the connectedness of citation networks of RCTs by examining direct (referenced trials) and indirect (through references of referenced trials, etc) citation of trials to one another. METHODS Meta-analyses were used to create citation networks of RCTs addressing the same clinical questions. The primary measure was the proportion of networks where following citation links between RCTs identifies the complete set of RCTs, forming a single connected citation group. Other measures included the number of disconnected groups (islands) within each network, the number of citations in the network relative to the maximum possible, and the maximum number of links in the path between two connected trials (a measure of indirectness of citations). RESULTS We included 259 meta-analyses with a total of 2,413 and a median of seven RCTs each. For 46% (118 of 259) of networks, the RCTs formed a single connected citation group-one island. For the other 54% of networks, where at least one RCT group was not cited by others, 39% had two citation islands and 4% (10 of 257) had 10 or more islands. On average, the citation networks had 38% of the possible citations to other trials (if each trial had cited all earlier trials). The number of citation islands and the maximum number of citation links increased with increasing numbers of trials in the network. CONCLUSION Available evidence to answer a clinical question may be identified by using network citations created with a small initial corpus of eligible trials. However, the number of islands means that citation networks cannot be relied on for evidence retrieval.

Automatic evidence retrieval for systematic reviews

Background Snowballing involves recursively pursuing relevant references cited in the retrieved literature and adding them to the search results. Snowballing is an alternative approach to discover additional evidence that was not retrieved through conventional search. Snowballing’s effectiveness makes it best practice in systematic reviews despite being time-consuming and tedious. Objective Our goal was to evaluate an automatic method for citation snowballing’s capacity to identify and retrieve the full text and/or abstracts of cited articles. Methods Using 20 review articles that contained 949 citations to journal or conference articles, we manually searched Microsoft Academic Search (MAS) and identified 78.0% (740/949) of the cited articles that were present in the database. We compared the performance of the automatic citation snowballing method against the results of this manual search, measuring precision, recall, and F1 score. Results The automatic method was able to correctly identify 633 (as proportion of included citations: recall=66.7%, F1 score=79.3%; as proportion of citations in MAS: recall=85.5%, F1 score=91.2%) of citations with high precision (97.7%), and retrieved the full text or abstract for 490 (recall=82.9%, precision=92.1%, F1 score=87.3%) of the 633 correctly retrieved citations. Conclusions The proposed method for automatic citation snowballing is accurate and is capable of obtaining the full texts or abstracts for a substantial proportion of the scholarly citations in review articles. By automating the process of citation snowballing, it may be possible to reduce the time and effort of common evidence surveillance tasks such as keeping trial registries up to date and conducting systematic reviews.

Context-driven discovery of gene cassettes in mobile integrons using a computational grammar

BackgroundGene discovery algorithms typically examine sequence data for low level patterns. A novel method to computationally discover higher order DNA structures is presented, using a context sensitive grammar. The algorithm was applied to the discovery of gene cassettes associated with integrons. The discovery and annotation of antibiotic resistance genes in such cassettes is essential for effective monitoring of antibiotic resistance patterns and formulation of public health antibiotic prescription policies.ResultsWe discovered two new putative gene cassettes using the method, from 276 integron features and 978 GenBank sequences. The system achieved κ = 0.972 annotation agreement with an expert gold standard of 300 sequences. In rediscovery experiments, we deleted 789,196 cassette instances over 2030 experiments and correctly relabelled 85.6% (α ≥ 95%, E ≤ 1%, mean sensitivity = 0.86, specificity = 1, F-score = 0.93), with no false positives.Error analysis demonstrated that for 72,338 missed deletions, two adjacent deleted cassettes were labeled as a single cassette, increasing performance to 94.8% (mean sensitivity = 0.92, specificity = 1, F-score = 0.96).ConclusionUsing grammars we were able to represent heuristic background knowledge about large and complex structures in DNA. Importantly, we were also able to use the context embedded in the model to discover new putative antibiotic resistance gene cassettes. The method is complementary to existing automatic annotation systems which operate at the sequence level.

Modelling heating of liver tumours with heterogeneous magnetic microsphere deposition

Ferromagnetic embolization hyperthermia (FEH) is a novel treatment for liver cancer. Magnetic microspheres are injected into the hepatic artery and cluster in the periphery of tumours and are heated with externally applied magnetic fields. In order to more accurately simulate FEH, we modelled a three-dimensional heterogeneous distribution of heat sources. We constructed a fractal model of the vasculature in the periphery of a tumour. We used this model to compute the spatial distribution of the microspheres that lodge in capillaries. We used the distribution model as input to a finite-element heat transfer model of the FEH treatment. The overall appearance of the vascular tree is subjectively similar to that of the disorganized vascular network which encapsulates tumours. The microspheres are distributed in the tumour periphery in similar patterns to experimental observations. We expect the vasculature and microsphere deposition models to also be of interest to researchers of any targeted cancer therapies such as localized intra-arterial chemotherapy and selective internal radiotherapy. Our results show that heterogeneous microsphere distributions give significantly different results to those for a homogeneous model and thus are preferable when accurate results are required.