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PubMed2006

Snapshots and snippets: general practitioners' reflections on professional space.

The paper presents the results of a mixed methods study of British general practitioners' (GPs) reflections on professional space in terms of practice and self-identity. Inter-textual content analysis of 12 biographic and photographic datasets revealed four themes: workspace, re-appropriated space, life space and sacred space. GPs are ambivalent about their working environments, spending time and energy creating 'best fit' spaces, until lack of function becomes an habituated part of daily routine. Whilst some appear helpless in the face of change, others are making their presence felt through embodied, personalized or authorial spaces.

Attitude of Health Personnel↗
PubMed2005

Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: a two-stage study.

Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n=515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n=264) of these subjects. AD patients (n=100) and controls (n=48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p=0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p=0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p=0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p=0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2.

Aged↗
PubMed1998

Identification of variables needed to risk adjust outcomes of coronary interventions: evidence-based guidelines for efficient data collection.

OBJECTIVES: Our objectives were to identify and define a minimum set of variables for interventional cardiology that carried the most statistical weight for predicting adverse outcomes. Though "gaming" cannot be completely avoided, variables were to be as objective as possible and reproducible and had to be predictive of outcome in current databases. BACKGROUND: Outcomes of percutaneous coronary interventions depend on patient risk characteristics and disease severity and acuity. Comparing results of interventions has been difficult because definitions of similar variables differ in databases, and variables are not uniformly tracked. Identifying the best predictor variables and standardizing their definitions are a first step in developing a universal stratification instrument. METHODS: A list of empirically derived variables was first tested in eight cardiac databases (158,273 cases). Three end points (in-hospital death, in-hospital coronary artery bypass graft surgery, Q wave myocardial infarction) were chosen for analysis. Univariate and multivariate regression models were used to quantify the predictive value of the variable in each database. The variables were then defined by consensus by a panel of experts. RESULTS: In all databases patient demographics were similar, but disease severity varied greatly. The most powerful predictors of adverse outcome were measures of hemodynamic instability, disease severity, demographics and comorbid conditions in both univariate and multivariate analyses. CONCLUSIONS: Our analysis identified 29 variables that have the strongest statistical association with adverse outcomes after coronary interventions. These variables were also objectively defined. Incorporation of these variables into every cardiac dataset will provide uniform standards for data collected. Comparisons of outcomes among physicians, institutions and databases will therefore be more meaningful.

Adult↗
PubMed2004

AMASS: software for automatically validating the quality of MS/MS spectrum from SEQUEST results.

Time-consuming and experience-dependent manual validations of tandem mass spectra are usually applied to SEQUEST results. This inefficient method has become a significant bottleneck for MS/MS data processing. Here we introduce a program AMASS (advanced mass spectrum screener), which can filter the tandem mass spectra of SEQUEST results by measuring the match percentage of high-abundant ions and the continuity of matched fragment ions in b, y series. Compared with Xcorr and DeltaCn filter, AMASS can increase the number of positives and reduce the number of negatives in 22 datasets generated from 18 known protein mixtures. It effectively removed most noisy spectra, false interpretations, and about half of poor fragmentation spectra, and AMASS can work synergistically with Rscore filter. We believe the use of AMASS and Rscore can result in a more accurate identification of peptide MS/MS spectra and reduce the time and energy for manual validation.

Algorithms↗
PubMed2001

The Zebrafish Information Network (ZFIN): a resource for genetic, genomic and developmental research.

The Zebrafish Information Network, ZFIN, is a WWW community resource of zebrafish genetic, genomic and developmental research information (http://zfin.org). ZFIN provides an anatomical atlas and dictionary, developmental staging criteria, research methods, pathology information and a link to the ZFIN relational database (http://zfin. org/ZFIN/). The database, built on a relational, object-oriented model, provides integrated information about mutants, genes, genetic markers, mapping panels, publications and contact information for the zebrafish research community. The database is populated with curated published data, user submitted data and large dataset uploads. A broad range of data types including text, images, graphical representations and genetic maps supports the data. ZFIN incorporates links to other genomic resources that provide sequence and ortholog data. Zebrafish nomenclature guidelines and an automated registration mechanism for new names are provided. Extensive usability testing has resulted in an easy to learn and use forms interface with complex searching capabilities.

Animals↗
PubMed2005

The efficiency of different search strategies in estimating parsimony jackknife, bootstrap, and Bremer support.

BACKGROUND: For parsimony analyses, the most common way to estimate confidence is by resampling plans (nonparametric bootstrap, jackknife), and Bremer support (Decay indices). The recent literature reveals that parameter settings that are quite commonly employed are not those that are recommended by theoretical considerations and by previous empirical studies. The optimal search strategy to be applied during resampling was previously addressed solely via standard search strategies available in PAUP*. The question of a compromise between search extensiveness and improved support accuracy for Bremer support received even less attention. A set of experiments was conducted on different datasets to find an empirical cut-off point at which increased search extensiveness does not significantly change Bremer support and jackknife or bootstrap proportions any more. RESULTS: For the number of replicates needed for accurate estimates of support in resampling plans, a diagram is provided that helps to address the question whether apparently different support values really differ significantly. It is shown that the use of random addition cycles and parsimony ratchet iterations during bootstrapping does not translate into higher support, nor does any extension of the search extensiveness beyond the rather moderate effort of TBR (tree bisection and reconnection branch swapping) plus saving one tree per replicate. Instead, in case of very large matrices, saving more than one shortest tree per iteration and using a strict consensus tree of these yields decreased support compared to saving only one tree. This can be interpreted as a small risk of overestimating support but should be more than compensated by other factors that counteract an enhanced type I error. With regard to Bremer support, a rule of thumb can be derived stating that not much is gained relative to the surplus computational effort when searches are extended beyond 20 ratchet iterations per constrained node, at least not for datasets that fall within the size range found in the current literature. CONCLUSION: In view of these results, calculating bootstrap or jackknife proportions with narrow confidence intervals even for very large datasets can be achieved with less expense than often thought. In particular, iterated bootstrap methods that aim at reducing statistical bias inherent to these proportions are more feasible when the individual bootstrap searches require less time.

Bayes Theorem↗
PubMed2005

Linkage mapping of a complex trait in the New York population of the GAW14 simulated dataset: a multivariate phenotype approach.

Multivariate phenotypes underlie complex traits. Thus, instead of using the end-point trait, it may be statistically more powerful to use a multivariate phenotype correlated to the end-point trait for detecting linkage. In this study, we develop a reverse regression method to analyze linkage of Kofendrerd Personality Disorder affection status in the New York population of the Genetic Analysis Workshop 14 (GAW14) simulated dataset. When we used the multivariate phenotype, we obtained significant evidence of linkage near four of the six putative loci in at least 25% of the replicates. On the other hand, the linkage analysis based on Kofendrerd Personality Disorder status as a phenotype produced significant findings only near two of the loci and in a smaller proportion of replicates.

Chromosome Mapping↗
PubMed2005

High-recall protein entity recognition using a dictionary.

SUMMARY: Protein name extraction is an important step in mining biological literature. We describe two new methods for this task: semiCRFs and dictionary HMMs. SemiCRFs are a recently-proposed extension to conditional random fields (CRFs) that enables more effective use of dictionary information as features. Dictionary HMMs are a technique in which a dictionary is converted to a large HMM that recognizes phrases from the dictionary, as well as variations of these phrases. Standard training methods for HMMs can be used to learn which variants should be recognized. We compared the performance of our new approaches with that of Maximum Entropy (MaxEnt) and normal CRFs on three datasets, and improvement was obtained for all four methods over the best published results for two of the datasets. CRFs and semiCRFs achieved the highest overall performance according to the widely-used F-measure, while the dictionary HMMs performed the best at finding entities that actually appear in the dictionary-the measure of most interest in our intended application. AVAILABILITY: Dictionary HMMs were implemented in Java. Algorithms are available through an information extraction package MINORTHIRD on http://minorthird.sourceforge.net

Algorithms↗
PubMed1994

Calculation of benchmark doses from teratology data.

The benchmark dose approach has several potential advantages over the no observed adverse effect level (NOAEL) as a basis for risk assessment of toxic chemicals, based upon animal toxicity data. The practical use of the benchmark dose has been evaluated by applying dose-response models to an extensive historical database of teratology bioassays. Doses corresponding to 1 and 5% increases in incidence of lesions are calculated and compared to NOAELs. The statistical accuracy of these estimates was determined by calculating confidence intervals. The lower confidence limit on the 5% benchmark dose (LED05) is found to be comparable to the NOAEL for most datasets, and slightly higher on average. Benchmark doses at the 1% level could not be estimated accurately (i.e., they had wide confidence intervals) for a significant fraction of the datasets. LED01 values were lower on average than the NOAEL. Based on these results, it is concluded that benchmark doses for a 5% increases in incidence can be calculated for most datasets, and could be used as a satisfactory basis for risk assessment, e.g., to set reference doses or acceptable daily intakes. An exception occurs when the benchmark dose exceeds the highest dose of the study. This is only likely to occur when the chemical causes a small, but significant, increase in a finding that is uncommon in untreated animals.

Abnormalities, Drug-Induced↗
PubMed2004

Improved and automated prediction of effective siRNA.

Short interfering RNAs are used in functional genomics studies to knockdown a single gene in a reversible manner. The results of siRNA experiments are highly dependent on the choice of siRNA sequence. In order to evaluate siRNA design rules, we collected a database of 398 siRNAs of known efficacy from 92 genes. We used this database to evaluate previously proposed rules from smaller datasets, and to find a new set of rules that are optimal for the entire database. We also trained a regression tree with full cross-validation. It was however difficult to obtain the same precision as methods previously tested on small datasets from one or two genes. We show that those methods are overfitting as they work poorly on independent validation datasets from multiple genes. Our new design rules can predict siRNAs with efficacy >/= 50% in 91% of cases, and with efficacy >/=90% in 52% of cases, which is more than a twofold improvement over random selection. Software for designing siRNAs is available online via a web server at or as a standalone version for high-throughput applications.

Algorithms↗
PubMed2002

Congenital Heart Surgery Nomenclature and Database Project: update and proposed data harvest.

In 1998, the first report of the Society of Thoracic Surgery (STS) National Congenital Heart Surgery Database reported the clinical features of 18 congenital heart categories. The report provided a significant amount of important information and also highlighted the strengths and weaknesses of the existing database. Following this report, the STS Congenital Heart Surgery Committee, in cooperation with the European Association of Cardio-Thoracic Surgery and the European Congenital Heart Surgeons Foundation, initiated the International Congenital Heart Surgery and Nomenclature Database Project. The goal was to begin the standardization of nomenclature and reporting strategies and establish the foundations for an international congenital heart surgery database. The first report of the International Congenital Heart Surgery Nomenclature Project was published in the Annals of Thoracic Surgery in April 2000. The current report outlines modifications to the minimal dataset, as well as the diagnosis and procedure short lists.

Cardiac Surgical Procedures↗
PubMed2026

The Evolutionary Significance of Leaf Nodulation: Evidence from Ardisia and Its Relatives (Primulaceae: Myrsinoideae).

Interactions between plants and microorganisms have long been a central topic in biological research. Bacterial symbiosis on leaf surfaces represents a distinctive and mutually beneficial system within the phyllosphere microbiome. Leaf nodules are the visible manifestation of the symbiosis and confer ecological advantages to host plants by enhancing host resistance against pathogens and herbivores. It has been hypothesized that these advantages promote higher diversification rates in host lineages, but this remains uncertain. Ardisia subg. Crispardisia and its close relatives (Amblyanthopsis and Amblyanthus) within Primulaceae are typical plant groups with leaf nodule symbiosis, making them an ideal system for testing this hypothesis. In this study, we conducted extensive sampling of "Ardisioids" (Ardisia and its allies) and reconstructed their phylogenetic relationships and evolutionary history using plastid genomes and nuclear datasets (i.e., nuclear ribosomal DNA (nrDNA) and genome-wide single nucleotide polymorphisms (SNPs)). We clarified the phylogenetic positions of several "Ardisioids" genera (e.g., Sadiria, Tapeinosperma, Amblyanthus, and Amblyanthopsis) and multiple subgenera within Ardisia. We further detected a rapid radiation during the middle Miocene in Ardisia and its allies. Notably, we found that the leaf-nodulated clade appears to have originated during this period, approximately 11-8 Ma. BAMM (Bayesian Analysis of Macroevolutionary Mixtures) analyses revealed elevated diversification rates in leaf-nodulated lineages, while HiSSE (Hidden State Speciation and Extinction) analyses indicated that leaf nodule symbiosis might have increased speciation rates without significantly affecting extinction rates. These results provide strong evidence that leaf nodule symbiosis, together with other abiotic and biotic factors, represents a key evolutionary innovation that has promoted diversification in Ardisia and its close relatives.

diversification rate↗
PubMed2005

Three-dimensional analysis of mandibular growth and tooth eruption.

Normal and abnormal jaw growth and tooth eruption are topics of great importance for several dental and medical disciplines. Thus far, clinical studies on these topics have used two-dimensional (2D) radiographic techniques. The purpose of the present study was to analyse normal mandibular growth and tooth eruption in three dimensions based on computer tomography (CT) scans, extending the principles of mandibular growth analysis proposed by Björk in 1969 from two to three dimensions. As longitudinal CT data from normal children are not available (for ethical reasons), CT data from children with Apert syndrome were employed, because it has been shown that the mandible in Apert syndrome is unaffected by the malformation, and these children often have several craniofacial CT scans performed during childhood for planning of cranial and midface surgery and for follow-up after surgery. A total of 49 datasets from ten children with Apert syndrome were available for study. The number of datasets from each individual ranged from three to seven. The first CT scan in each of the ten series was carried out before 1 year of age, and the ages for the 49 scans ranged from 1 week to 14.5 years. The mandible and the teeth were segmented and iso-surfaces generated. Landmarks were placed on the surface of the mandible, along the mandibular canals, the inner contour of the cortical plate at the lower border of the symphysis menti, and on the teeth. Superimposition of the mandibles in the longitudinal series was performed using the symphysis menti and the mandibular canals as suggested by Björk. The study supported the findings of stability of the symphysis menti and the mandibular canals as seen in profile view previously reported by Björk & Skieller in 1983. However, the mandibular canals were, actually, relocated laterally during growth. Furthermore, the position of tooth buds remained relatively stable inside the jaw until root formation started. Eruption paths of canines and premolars were vertical, whereas molars erupted in a lingual direction. The 3D method would seem to offer new insight into jaw growth and tooth eruption, but further studies are needed.

Acrocephalosyndactylia↗
PubMed2006

Development of the Stroke-unit Discharge Guideline: choice of assessment instruments for prediction in the subacute phase post-stroke.

The purpose of this paper is to present the design of an evidence-based dataset of assessment instruments for the prognostic factors of the Stroke-unit Discharge Guideline (SDG), a consensus based guideline for the decision of the discharge destination from the hospital stroke unit. In our systematic literature reviews and in known standard works we have looked for assessment instruments which are being used most frequently in stroke care, and subsequently we have searched for information regarding their validity and reliability. For 17 out of the 26 prognostic factors we found known applicable assessment instruments. Clinical feasibility and psychometric properties of most of these instruments are sufficient to good. For two factors we had to construct a new instrument. A simple definition was sufficient for the remaining seven factors. The SDG contains an evidence-based dataset of prognostic factors and assessment instruments, and should be applied at the hospital stroke-unit, which is the first location to start with a uniform use of stroke assessment instruments. The SDG assessment instruments are part of the stroke service chain information system, which contains recently developed specifications for application in web-based electronic patient records nationwide in The Netherlands.

Disability Evaluation↗
PubMed1993

An approach to the use of the DO IT Study Group guidelines for supporting the optimal implementation of information systems in diabetes care.

The usefulness of the 1992 DO IT Study Group guidelines for diabetes data information systems was assessed using two established diabetes databases designed for different purposes. The recommendations detailed in the guidelines, written in four separate but overlapping modules, were applied individually to each database in turn. Percentage compliance with the recommendation to collect the DIABCARE dataset was high, after discounting specialist areas. While on the whole the information systems complied with the guidelines within the purposes for which they were designed, areas highlighted as demanding further action in at least one of the two systems included password protection, data validation checks, screen design, and communication with those whose records were held on the systems. Application of the guidelines is already stimulating attention to some of these areas. Some of the guidelines proved rather vague in construction to be applied in any formal sense, while others (for example in relation to international accreditation of datasets) were not applicable to individual systems. The results suggest the importance of a structured approach to the design, development, and ongoing assessment of information systems in diabetes, but require the present guidelines to develop a more formal structure to be fully effective. The widespread adoption and further testing and refinement of these guidelines (both within and outside Europe) should promote the ultimate goal of improved diabetes care.

Communication↗
PubMed1996

The NCIC-Manitoba Breast Tumor Bank: a resource for applied cancer research.

The NCIC-Manitoba Breast Tumor Bank is one of several tumour banks that have been established through the Molecular Epidemiology Program of the National Cancer Institute of Canada (NCIC). The NCIC-Manitoba Breast Tumor Bank is an example of one model developed to facilitate research designed to translate the findings of basic science into information useful in the clinical arena. The tumour bank's mandate is to provide a national resource that consists of a preassembled dataset of matched samples of paraffin-embedded and frozen tumour tissue with corresponding pathological and clinical data. In the first 3 years the tumour bank has accrued data and samples from over 1800 cases of breast cancer and has provided support for 20 research projects across Canada and the United States.

Academies and Institutes↗
PubMed1995

Predictability, complexity, and catastrophe in a collapsible model of population, development, and environmental interactions.

"More and more population forecasts are being produced with associated 95 percent confidence intervals. How confident are we of those confidence intervals? In this paper, we produce a simulated dataset in which we know both past and future population sizes, and the true 95 percent confidence intervals at various future dates. We use the past data to produce population forecasts and estimated 95 percent confidence intervals using various functional forms. We, then, compare the true 95 percent confidence intervals with the estimated ones. This comparison shows that we are not at all confident of the estimated 95 percent confidence intervals." (SUMMARY IN FRE)

Evaluation Studies as Topic↗
PubMed2006

A mixture model with random-effects components for clustering correlated gene-expression profiles.

MOTIVATION: The clustering of gene profiles across some experimental conditions of interest contributes significantly to the elucidation of unknown gene function, the validation of gene discoveries and the interpretation of biological processes. However, this clustering problem is not straightforward as the profiles of the genes are not all independently distributed and the expression levels may have been obtained from an experimental design involving replicated arrays. Ignoring the dependence between the gene profiles and the structure of the replicated data can result in important sources of variability in the experiments being overlooked in the analysis, with the consequent possibility of misleading inferences being made. We propose a random-effects model that provides a unified approach to the clustering of genes with correlated expression levels measured in a wide variety of experimental situations. Our model is an extension of the normal mixture model to account for the correlations between the gene profiles and to enable covariate information to be incorporated into the clustering process. Hence the model is applicable to longitudinal studies with or without replication, for example, time-course experiments by using time as a covariate, and to cross-sectional experiments by using categorical covariates to represent the different experimental classes. RESULTS: We show that our random-effects model can be fitted by maximum likelihood via the EM algorithm for which the E(expectation)and M(maximization) steps can be implemented in closed form. Hence our model can be fitted deterministically without the need for time-consuming Monte Carlo approximations. The effectiveness of our model-based procedure for the clustering of correlated gene profiles is demonstrated on three real datasets, representing typical microarray experimental designs, covering time-course, repeated-measurement and cross-sectional data. In these examples, relevant clusters of the genes are obtained, which are supported by existing gene-function annotation. A synthetic dataset is considered too. AVAILABILITY: A Fortran program blue called EMMIX-WIRE (EM-based MIXture analysis WIth Random Effects) is available on request from the corresponding author.

Algorithms↗