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Background Multiresistance in Gram-negative bacteria is often due to acquisition of several different antibiotic resistance genes, each associated with a different mobile genetic element, that tend to cluster together in complex conglomerations. Accurate, consistent annotation of resistance genes, the boundaries and fragments of mobile elements, and signatures of insertion, such as DR, facilitates comparative analysis of complex multiresistance regions and plasmids to better understand their evolution and how resistance genes spread. Objectives To extend the Repository of Antibiotic resistance Cassettes (RAC) web site, which includes a database of 'features', and the Attacca automatic DNA annotation system, to encompass additional resistance genes and all types of associated mobile elements. Methods Antibiotic resistance genes and mobile elements were added to RAC, from existing registries where possible. Attacca grammars were extended to accommodate the expanded database, to allow overlapping features to be annotated and to identify and annotate features such as composite transposons and DR. Results The Multiple Antibiotic Resistance Annotator (MARA) database includes antibiotic resistance genes and selected mobile elements from Gram-negative bacteria, distinguishing important variants. Sequences can be submitted to the MARA web site for annotation. A list of positions and orientations of annotated features, indicating those that are truncated, DR and potential composite transposons is provided for each sequence, as well as a diagram showing annotated features approximately to scale. Conclusions The MARA web site (http://mara.spokade.com) provides a comprehensive database for mobile antibiotic resistance in Gram-negative bacteria and accurately annotates resistance genes and associated mobile elements in submitted sequences to facilitate comparative analysis.

New approaches to evidence synthesis, which use human effort and machine automation in mutually reinforcing ways, can enhance the feasibility and sustainability of living systematic reviews. Human effort is a scarce and valuable resource, required when automation is impossible or undesirable, and includes contributions from online communities (“crowds”) as well as more conventional contributions from review authors and information specialists. Automation can assist with some systematic review tasks, including searching, eligibility assessment, identification and retrieval of full-text reports, extraction of data, and risk of bias assessment. Workflows can be developed in which human effort and machine automation can each enable the other to operate in more effective and efficient ways, offering substantial enhancement to the productivity of systematic reviews. This paper describes and discusses the potential—and limitations—of new ways of undertaking specific tasks in living systematic reviews, identifying areas where these human/machine “technologies” are already in use, and where further research and development is needed. While the context is living systematic reviews, many of these enabling technologies apply equally to standard approaches to systematic reviewing.

The third meeting of the International Collaboration for Automation of Systematic Reviews (ICASR) was held 17–18 October 2017 in London, England. ICASR is an interdisciplinary group whose goal is to maximize the use of technology for conducting rapid, accurate, and efficient systematic reviews of scientific evidence. The group seeks to facilitate the development and widespread acceptance of automated techniques for systematic reviews. The meeting’s conclusion was that the most pressing needs at present are to develop approaches for validating currently available tools and to provide increased access to curated corpora that can be used for validation. To that end, ICASR’s short-term goals in 2018–2019 are to propose and publish protocols for key tasks in systematic reviews and to develop an approach for sharing curated corpora for validating the automation of the key tasks.

Display Omitted Using EMR data to measure downtime effects on clinical processes.A matched case-control design is used to examine downtime effects.The effects of downtime vary with the type of IT problem.Even brief system downtimes may impact patient care.Having application potential to other clinical processes with established workflow. ObjectiveTo introduce and evaluate a method that uses electronic medical record (EMR) data to measure the effects of computer system downtime on clinical processes associated with pathology testing and results reporting. Materials and methodsA matched case-control design was used to examine the effects of five downtime events over 11-months, ranging from 5 to 300min. Four indicator tests representing different laboratory workflows were selected to measure delays and errors: potassium, haemoglobon, troponin and activated partial thromboplastin time. Tests exposed to a downtime were matched to tests during unaffected control periods by test type, time of day and day of week. Measures included clinician read time (CRT), laboratory turnaround time (LTAT), and rates of missed reads, futile searches, duplicate orders, and missing test results. ResultsThe effects of downtime varied with the type of IT problem. When clinicians could not logon to a results reporting system for 17-min, the CRT for potassium and haemoglobon tests was five (10.3 vs. 2.0days) and six times (13.4 vs. 2.1days) longer than control (p=0.01-0.04; p=0.0001-0.003). Clinician follow-up of tests was also delayed by another downtime involving a power outage with a small effect. In contrast, laboratory processing of troponin tests was unaffected by network services and routing problems. Errors including missed reads, futile searches, duplicate orders and missing test results could not be examined because the sample size of affected tests was not sufficient for statistical testing. ConclusionThis study demonstrates the feasibility of using routinely collected EMR data with a matched case-control design to measure the effects of downtime on clinical processes. Even brief system downtimes may impact patient care. The methodology has potential to be applied to other clinical processes with established workflows where tasks are pre-defined such as medications management.

This study examines the impact of cefepime and APP-β (antipseudomonal penicillin/ β-lactamase inhibitor combinations) on Gram-negative bacterial colonization and resistance in two Australian ICUs. While resistance did not cumulatively increase, cefepime (but not APP-β treatment) was associated with acquisition of antibiotic resistant Enterobacteriaceae, consistent with an ecological effect. Analysis of the resident gut E. coli population in a subset of patients showed an increase in markers of horizontal gene transfer after cefepime exposure that helps explain the increase in APP-β resistance and reminds us that unmeasured impacts on the microbiome are key outcome determinants that need to be fully explored. Electronic supplementary material The online version of this article (10.1186/s40635-018-0185-2) contains supplementary material, which is available to authorized users.

Background Although many aspects of systematic reviews use computational tools, systematic reviewers have been reluctant to adopt machine learning tools. Discussion We discuss that the potential reason for the slow adoption of machine learning tools into systematic reviews is multifactorial. We focus on the current absence of trust in automation and set-up challenges as major barriers to adoption. It is important that reviews produced using automation tools are considered non-inferior or superior to current practice. However, this standard will likely not be sufficient to lead to widespread adoption. As with many technologies, it is important that reviewers see “others” in the review community using automation tools. Adoption will also be slow if the automation tools are not compatible with workflows and tasks currently used to produce reviews. Many automation tools being developed for systematic reviews mimic classification problems. Therefore, the evidence that these automation tools are non-inferior or superior can be presented using methods similar to diagnostic test evaluations, i.e., precision and recall compared to a human reviewer. However, the assessment of automation tools does present unique challenges for investigators and systematic reviewers, including the need to clarify which metrics are of interest to the systematic review community and the unique documentation challenges for reproducible software experiments. Conclusion We discuss adoption barriers with the goal of providing tool developers with guidance as to how to design and report such evaluations and for end users to assess their validity. Further, we discuss approaches to formatting and announcing publicly available datasets suitable for assessment of automation technologies and tools. Making these resources available will increase trust that tools are non-inferior or superior to current practice. Finally, we identify that, even with evidence that automation tools are non-inferior or superior to current practice, substantial set-up challenges remain for main stream integration of automation into the systematic review process.

The second meeting of the International Collaboration for Automation of Systematic Reviews (ICASR) was held 3–4 October 2016 in Philadelphia, Pennsylvania, USA. ICASR is an interdisciplinary group whose aim is to maximize the use of technology for conducting rapid, accurate, and efficient systematic reviews of scientific evidence. Having automated tools for systematic review should enable more transparent and timely review, maximizing the potential for identifying and translating research findings to practical application. The meeting brought together multiple stakeholder groups including users of summarized research, methodologists who explore production processes and systematic review quality, and technologists such as software developers, statisticians, and vendors. This diversity of participants was intended to ensure effective communication with numerous stakeholders about progress toward automation of systematic reviews and stimulate discussion about potential solutions to identified challenges. The meeting highlighted challenges, both simple and complex, and raised awareness among participants about ongoing efforts by various stakeholders. An outcome of this forum was to identify several short-term projects that participants felt would advance the automation of tasks in the systematic review workflow including (1) fostering better understanding about available tools, (2) developing validated datasets for testing new tools, (3) determining a standard method to facilitate interoperability of tools such as through an application programming interface or API, and (4) establishing criteria to evaluate the quality of tools’ output. ICASR 2016 provided a beneficial forum to foster focused discussion about tool development and resources and reconfirm ICASR members’ commitment toward systematic reviews’ automation.

Objectives To examine the use of supervised machine learning to identify biases in evidence selection and determine if citation information can predict favorable conclusions in reviews about neuraminidase inhibitors. Study Design and Setting Reviews of neuraminidase inhibitors published during January 2005 to May 2013 were identified by searching PubMed. In a blinded evaluation, the reviews were classified as favorable if investigators agreed that they supported the use of neuraminidase inhibitors for prophylaxis or treatment of influenza. Reference lists were used to identify all unique citations to primary articles. Three classification methods were tested for their ability to predict favorable conclusions using only citation information. Results Citations to 4,574 articles were identified in 152 reviews of neuraminidase inhibitors, and 93 (61%) of these reviews were graded as favorable. Primary articles describing drug resistance were among the citations that were underrepresented in favorable reviews. The most accurate classifier predicted favorable conclusions with 96.2% accuracy, using citations to only 24 of 4,574 articles. Conclusion Favorable conclusions in reviews about neuraminidase inhibitors can be predicted using only information about the articles they cite. The approach highlights how evidence exclusion shapes conclusions in reviews and provides a method to evaluate citation practices in a corpus of reviews.

Background Screening candidate studies for inclusion in a systematic review is time-consuming when conducted manually. Automation tools could reduce the human effort devoted to screening. Existing methods use supervised machine learning which train classifiers to identify relevant words in the abstracts of candidate articles that have previously been labelled by a human reviewer for inclusion or exclusion. Such classifiers typically reduce the number of abstracts requiring manual screening by about 50%. Methods We extracted four key characteristics of observational studies (population, exposure, confounders and outcomes) from the text of titles and abstracts for all articles retrieved using search strategies from systematic reviews. Our screening method excluded studies if they did not meet a predefined set of characteristics. The method was evaluated using three systematic reviews. Screening results were compared to the actual inclusion list of the reviews. Results The best screening threshold rule identified studies that mentioned both exposure (E) and outcome (O) in the study abstract. This screening rule excluded 93.7% of retrieved studies with a recall of 98%. Conclusions Filtering studies for inclusion in a systematic review based on the detection of key study characteristics in abstracts significantly outperformed standard approaches to automated screening and appears worthy of further development and evaluation.

While it is important for the evidence supporting practice guidelines to be current, that is often not the case. The advent of living systematic reviews has made the concept of "living guidelines" realistic, with the promise to provide timely, up-to-date and high-quality guidance to target users. We define living guidelines as an optimization of the guideline development process to allow updating individual recommendations as soon as new relevant evidence becomes available. A major implication of that definition is that the unit of update is the individual recommendation and not the whole guideline. We then discuss when living guidelines are appropriate, the workflows required to support them, the collaboration between living systematic reviews and living guideline teams, the thresholds for changing recommendations, and potential approaches to publication and dissemination. The success and sustainability of the concept of living guideline will depend on those of its major pillar, the living systematic review. We conclude that guideline developers should both experiment with and research the process of living guidelines.

Genome is the carrier of somatic mutations during the development of cancer. The catalogue of simple somatic mutations (SSM) is a subgroup of somatic mutations. It includes single base substitutions, small deletions and insertions of T substitutions at NpCpG trinucleotide contexts. Skin cancer showed distinct mutational spectra. Breast cancer, bladder cancer, and cervical cancer were found to have similar mutational spectra. Acute myeloid leukemia and lung cancer from South Korea, and colorectal cancer from China show high density of single base substitutions per mega base in chromosome Y. To sum up, our study and findings will be thought provoking in studying SSM in cancer.

A living systematic review (LSR) should keep the review current as new research evidence emerges. Any meta-analyses included in the review will also need updating as new material is identified. If the aim of the review is solely to present the best current evidence standard meta-analysis may be sufficient, provided reviewers are aware that results may change at later updates. If the review is used in a decision-making context, more caution may be needed. When using standard meta-analysis methods, the chance of incorrectly concluding that any updated meta-analysis is statistically significant when there is no effect (the type I error) increases rapidly as more updates are performed. Inaccurate estimation of any heterogeneity across studies may also lead to inappropriate conclusions. This paper considers four methods to avoid some of these statistical problems when updating meta-analyses: two methods, that is, law of the iterated logarithm and the Shuster method control primarily for inflation of type I error and two other methods, that is, trial sequential analysis and sequential meta-analysis control for type I and II errors (failing to detect a genuine effect) and take account of heterogeneity. This paper compares the methods and considers how they could be applied to LSRs.

Systematic reviews are difficult to keep up to date, but failure to do so leads to a decay in review currency, accuracy, and utility. We are developing a novel approach to systematic review updating termed "Living systematic review" (LSR): systematic reviews that are continually updated, incorporating relevant new evidence as it becomes available. LSRs may be particularly important in fields where research evidence is emerging rapidly, current evidence is uncertain, and new research may change policy or practice decisions. We hypothesize that a continual approach to updating will achieve greater currency and validity, and increase the benefits to end users, with feasible resource requirements over time.

Objective: Quality improvement of health care requires robust measurable indicators to track performance. However identifying which indicators are supported by strong clinical evidence, typically from clinical trials, is often laborious. This study tests a novel method for automatically linking indicators to clinical trial registrations. Design: A set of 522 quality of care indicators for 22 common conditions drawn from the CareTrack study were automatically mapped to outcome measures reported in 13 971 trials from ClinicalTrials.gov. Intervention: Text mining methods extracted phrases mentioning indicators and outcome phrases, and these were compared using the Levenshtein edit distance ratio to measure similarity. Main Outcome Measure: Number of care indicators that mapped to outcome measures in clinical trials. Results: While only 13% of the 522 CareTrack indicators were thought to have Level I or II evidence behind them, 353 (68%) could be directly linked to randomized controlled trials. Within these 522, 50 of 70 (71%) Level I and II evidence-based indicators, and 268 of 370 (72%) Level V (consensus-based) indicators could be linked to evidence. Of the indicators known to have evidence behind them, only 5.7% (4 of 70) were mentioned in the trial reports but were missed by our method. Conclusions: We automatically linked indicators to clinical trial registrations with high precision. Whilst the majority of quality indicators studied could be directly linked to research evidence, a small portion could not and these require closer scrutiny. It is feasible to support the process of indicator development using automated methods to identify research evidence. Refereed/Peer-reviewed

Display Omitted Implemented a generic rule-based method to extract epidemiological characteristics.Created environmental health exposure specific dictionaries.Precision ranging from 81% to 100% across six characteristics.Automated extraction is a feasible approach towards automation of systematic reviews. IntroductionMost data extraction efforts in epidemiology are focused on obtaining targeted information from clinical trials. In contrast, limited research has been conducted on the identification of information from observational studies, a major source for human evidence in many fields, including environmental health. The recognition of key epidemiological information (e.g., exposures) through text mining techniques can assist in the automation of systematic reviews and other evidence summaries. MethodWe designed and applied a knowledge-driven, rule-based approach to identify targeted information (study design, participant population, exposure, outcome, confounding factors, and the country where the study was conducted) from abstracts of epidemiological studies included in several systematic reviews of environmental health exposures. The rules were based on common syntactical patterns observed in text and are thus not specific to any systematic review. To validate the general applicability of our approach, we compared the data extracted using our approach versus hand curation for 35 epidemiological study abstracts manually selected for inclusion in two systematic reviews. ResultsThe returned F-score, precision, and recall ranged from 70% to 98%, 81% to 100%, and 54% to 97%, respectively. The highest precision was observed for exposure, outcome and population (100%) while recall was best for exposure and study design with 97% and 89%, respectively. The lowest recall was observed for the population (54%), which also had the lowest F-score (70%). ConclusionThe generated performance of our text-mining approach demonstrated encouraging results for the identification of targeted information from observational epidemiological study abstracts related to environmental exposures. We have demonstrated that rules based on generic syntactic patterns in one corpus can be applied to other observational study design by simple interchanging the dictionaries aiming to identify certain characteristics (i.e., outcomes, exposures). At the document level, the recognised information can assist in the selection and categorization of studies included in a systematic review.

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. © 2009 American Institute of Physics.

Motivation: Larger than gene structures (LGS) are DNA segments that include at least one gene and often other segments such as inverted repeats and gene promoters. Mobile genetic elements (MGE) such as integrons are LGS that play an important role in horizontal gene transfer, primarily in Gram-negative organisms. Known LGS have a profound effect on organism virulence, antibiotic resistance and other properties of the organism due to the number of genes involved. Expert-compiled grammars have been shown to be an effective computational representation of LGS, well suited to automating annotation, and supporting de novo gene discovery. However, development of LGS grammars by experts is labour intensive and restricted to known LGS. Objectives: This study uses computational grammar inference methods to automate LGS discovery. We compare the ability of six algorithms to infer LGS grammars from DNA sequences annotated with genes and other short sequences. We compared the predictive power of learned grammars against an expert-developed grammar for gene cassette arrays found in Class 1, 2 and 3 integrons, which are modular LGS containing up to 9 of about 240 cassette types. Results: Using a Bayesian generalization algorithm our inferred grammar was able to predict > 95% of MGE structures in a corpus of 1760 sequences obtained from Genbank (F-score 75%). Even with 100% noise added to the training and test sets, we obtained an F-score of 68%, indicating that the method is robust and has the potential to predict de novo LGS structures when the underlying gene features are known. Availability: http://www2.chi.unsw.edu.au/attacca. Contact: guyt@unsw.edu.au

Gene cassettes are small mobile elements, consisting of little more than a single gene and recombination site, which are captured by larger elements called integrons. Several cassettes may be inserted into the same integron forming a tandem array. The discovery of integrons in the chromosome of many species has led to the identification of thousands of gene cassettes, mostly of unknown function, while integrons associated with transposons and plasmids carry mainly antibiotic resistance genes and constitute an important means of spreading resistance. An updated compilation of gene cassettes found in sequences of such ‘mobile resistance integrons’ in GenBank was facilitated by a specially developed automated annotation system. At least 130 different (

The three-dimensional microstructure of minerals and materials can be visualised in a non-destructive manner using X-ray microtomography. The digitised nature of the tomographic image allows us to generate finite element models which precisely detail the material’s microstructure. With a high degree of automation, high resolution models can be created quickly and with little user interaction. The geometry is taken from the microtomographic data, and loads and boundary conditions are applied to the model to simulate various conditions. The finite element analysis results show the deformation and stress distribution in the material. The technique allows us to study the relationship between microstructure and bulk properties of porous minerals, to characterise them in terms of their strength and stiffness, and to simulate their behaviour under known loading conditions. In this paper we present an application of micro-finite element analysis in the study of porous minerals. Micro-finite element analysis can be used to study the behaviour of a variety of minerals, and is especially useful when applied to materials that have a distinct microstructure that affects their bulk properties.

X-ray micro-computed tomography (microCT) is a non-destructive method of visualising specimens in three dimensions at the micrometer scale. Finite element analysis (FEA) is a method for approximating the structural response of systems to mechanical loading. The two methods are readily combined in micro-finite element analysis (microFEA). The microCT image, already in the discretized form of voxels, can be directly converted into a finite element mesh allowing materials with complex microstructures to be modelled. In this paper we present an example of microFEA model construction and use in the study of coke, a porous mineral. MicroCT datasets of different coke blends were used to create finite element models. The models were used to examine the material’s structural response to compressive loading by studying the resultant stress distributions and material deformation. MicroFEA can be used to advance our understanding of the relationship between porous materials’ microstructure and their bulk properties.

The complexity of quantitative biomedical models, and the rate at which they are published, is increasing to a point where managing the information has become all but impossible without automation. International efforts are underway to standardise representation languages for a number of mathematical entities that represent a wide variety of physiological systems. This paper presents the Field Representation Language (FRL), a portable representation of values that change over space and/or time. FRL is an extensible mark-up language (XML) derivative with support for large numeric data sets in Hierarchical Data Format version 5 (HDF5). Components of FRL can be reused through unified resource identifiers (URI) that point to external resources such as custom basis functions, boundary geometries and numerical data. To demonstrate the use of FRL as an interchange we present three models that study hyperthermia cancer treatment: a fractal model of liver tumour microvasculature; a probabilistic model simulating the deposition of magnetic microspheres throughout it; and a finite element model of hyperthermic treatment. The microsphere distribution field was used to compute the heat generation rate field around the tumour. We used FRL to convey results from the microsphere simulation to the treatment model. FRL facilitated the conversion of the coordinate systems and approximated the integral over regions of the microsphere deposition field.

SummaryBuilding a sustainable health system in the 21st Century will require the reinvention of much of the present day system, and the intelligent use of information and communication technologies (ICT) to deliver high quality, safe, efficient and affordable health care. The Centre for Health Informatics (CHI) is Australia’s largest academic research group in this emerging discipline.Our research is underpinned by a planning process, based on different future scenarios for the health system, which helps us identify longer-term problems needing a sustained research effort. A research competency matrix is used to ensure that the Centre has the requisite core capabilities in the research methods and tools needed to pursue our research program.The Centre’s work is internationally recognized for its contributions in the development of intelligent search systems to support evidence-based healthcare, developing evaluation methodologies for ICT, and in understanding how communication shapes the safety and quality of health care delivery. Centre researchers also are working on safety models and standards for ICT in healthcare, mining complex gene micro array, medical literature and medical record data, building health system simulation methods to model the impact of health policy changes, and developing novel computational methods to automate the diagnosis of 3-D medical images.Any individual research group like CHI must necessarily focus on a few areas to allow it to develop sufficient research capacity to make novel and internationally significant contributions. As CHI approaches the end of its first decade, it is becoming clear that developing capacity becomes increasingly challenging as the research territory changes under our feet, and that the Centre will continue to evolve and shift its focus in the years to come.

The manner in which people preferentially interact with others like themselves suggests that information about social connections may be useful in the surveillance of opinions for public health purposes. We examined if social connection information from tweets about human papillomavirus (HPV) vaccines could be used to train classifiers that identify anti-vaccine opinions. From 42,533 tweets posted between October 2013 and March 2014, 2,098 were sampled at random and two investigators independently identified anti-vaccine opinions. Machine learning methods were used to train classifiers using the first three months of data, including content (8,261 text fragments) and social connections (10,758 relationships). Connection-based classifiers performed similarly to content-based classifiers on the first three months of training data, and performed more consistently than content-based classifiers on test data from the subsequent three months. The most accurate classifier achieved an accuracy of 88.6% on the test data set, and used only social connection features. Information about how people are connected, rather than what they write, may be useful for improving public health surveillance methods on Twitter.

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.

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.

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.

Graphical abstractDisplay Omitted Knowledge-based functional enrichment for gene prioritization of high throughput data.Automatic ontology generation from MEDLINE.Novel and fully automatic literature-based discovery.Literature ontologies perform better than expert-derived ones. MotivationGene set enrichment analysis (GSEA) annotates gene microarray data with functional information from the biomedical literature to improve gene-disease association prediction. We hypothesize that supplementing GSEA with comprehensive gene function catalogs built automatically using information extracted from the scientific literature will significantly enhance GSEA prediction quality. MethodsGold standard gene sets for breast cancer (BrCa) and colorectal cancer (CRC) were derived from the literature. Two gene function catalogs (CMeSH and CUMLS) were automatically generated. 1. By using Entrez Gene to associate all recorded human genes with PubMed article IDs. 2. Using the genes mentioned in each PubMed article and associating each with the article's MeSH terms (in CMeSH) and extracted UMLS concepts (in CUMLS). Microarray data from the Gene Expression Omnibus for BrCa and CRC was then annotated using CMeSH and CUMLS and for comparison, also with several pre-existing catalogs (C2, C4 and C5 from the Molecular Signatures Database). Ranking was done using, a standard GSEA implementation (GSEA-p). Gene function predictions for enriched array data were evaluated against the gold standard by measuring area under the receiver operating characteristic curve (AUC). ResultsComparison of ranking using the literature enrichment catalogs, the pre-existing catalogs as well as five randomly generated catalogs show the literature derived enrichment catalogs are more effective. The AUC for BrCa using the unenriched gene expression dataset was 0.43, increasing to 0.89 after gene set enrichment with CUMLS. The AUC for CRC using the unenriched gene expression dataset was 0.54, increasing to 0.9 after enrichment with CMeSH. C2 increased AUC (BrCa 0.76, CRC 0.71) but C4 and C5 performed poorly (between 0.35 and 0.5). The randomly generated catalogs also performed poorly, equivalent to random guessing. DiscussionGene set enrichment significantly improved prediction of gene-disease association. Selection of enrichment catalog had a substantial effect on prediction accuracy. The literature based catalogs performed better than the MSigDB catalogs, possibly because they are more recent. Catalogs generated automatically from the literature can be kept up to date. ConclusionPrediction of gene-disease association is a fundamental task in biomedical research. GSEA provides a promising method when using literature-based enrichment catalogs. AvailabilityThe literature based catalogs generated and used in this study are available from http://www2.chi.unsw.edu.au/literature-enrichment.

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.

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.

Antibiotic resistance genes are embedded in mobile genetic elements (MGEs) that spread genes between organisms, even of different species. MGEs are large structures that consist of genes, and protein interaction sites. Although a considerable number of microbial DNA sequences have been published, searching for multi-resistant MGEs remains largely a manual task. This usually involves BLAST searches and a combination of keyword-based searches through sequence annotations and the literature. Using computational grammars, we can automate the recognition of arbitrarily complex sequence structures. In this chapter, we describe computational grammars, showing how they can be used to automate MGE annotation, and give examples of the annotation enabled by such grammars.

Background Gene 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. Results We 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). Conclusion Using 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.