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PubMed2004

Improving the statistical detection of regulated genes from microarray data using intensity-based variance estimation.

BACKGROUND: Gene microarray technology provides the ability to study the regulation of thousands of genes simultaneously, but its potential is limited without an estimate of the statistical significance of the observed changes in gene expression. Due to the large number of genes being tested and the comparatively small number of array replicates (e.g., N = 3), standard statistical methods such as the Student's t-test fail to produce reliable results. Two other statistical approaches commonly used to improve significance estimates are a penalized t-test and a Z-test using intensity-dependent variance estimates. RESULTS: The performance of these approaches is compared using a dataset of 23 replicates, and a new implementation of the Z-test is introduced that pools together variance estimates of genes with similar minimum intensity. Significance estimates based on 3 replicate arrays are calculated using each statistical technique, and their accuracy is evaluated by comparing them to a reliable estimate based on the remaining 20 replicates. The reproducibility of each test statistic is evaluated by applying it to multiple, independent sets of 3 replicate arrays. Two implementations of a Z-test using intensity-dependent variance produce more reproducible results than two implementations of a penalized t-test. Furthermore, the minimum intensity-based Z-statistic demonstrates higher accuracy and higher or equal precision than all other statistical techniques tested. CONCLUSION: An intensity-based variance estimation technique provides one simple, effective approach that can improve p-value estimates for differentially regulated genes derived from replicated microarray datasets. Implementations of the Z-test algorithms are available at http://vessels.bwh.harvard.edu/software/papers/bmcg2004.

DNA, Complementary↗
PubMed2003

Older adults' attitudes, concerns, and support for environmental issues in the "New West".

The natural environment has been a missing topic from education and public policy forums concerning an aging society. This study examines demographic trends and several socio-demographic influences on attitudes, concerns, and active support for environmental issues among older adults in a retirement "hot spot" in the New West. A sample of 394 older adults in southwestern Utah was obtained from questionnaires mailed to those randomly selected from a larger dataset, and through hand-distributed questionnaires at selected RV parks. We found a high degree of variability among respondents in regard to environmental attitudes and concerns. Despite a personal attitudinal desire to protect the environment, most older adults did not want to become involved in protective actions for the environment. We found that residency status and religious affiliation emerged as the strongest relationships with measures of attitudes and concerns, and willingness to support the environment. The most influential factors associated with willingness to take action in support of the environment were having higher levels of active/social concerns, and higher levels of awareness of environmental consequences. The New West is one of the fastest-growing areas for demographic aging, and the opinions and actions of older adults will play a significant role in the stewardship and sustainability of natural resources, particularly in retirement hot spots.

Aged↗
PubMed2004

Correlations between genomic GC levels and optimal growth temperatures are not 'robust'.

Musto et al. [FEBS Lett. 573 (2004) 73] studied the correlations between GC levels and optimal growth temperatures in 20 prokaryotic families. They reported that positive correlations are generally observed, and many of these are significant. Here, we have shown that these correlations are not "robust," i.e., correlation coefficients and/or significance of correlations can be considerably influenced by exclusion of very few (even as small as one) species from each dataset. The sensitivity of correlations is assumed as a result of high levels of bias in the family datasets. We concluded that solely based on these data, one cannot establish that GC contents of prokaryotic genomes increase as a result of growth temperature increments.

Adaptation, Physiological↗
PubMed2005

PatGen--a consolidated resource for searching genetic patent sequences.

UNLABELLED: Compared to the wealth of online resources covering genomic, proteomic and derived data the Bioinformatics community is rather underserved when it comes to patent information related to biological sequences. The current online resources are either incomplete or rather expensive. This paper describes, PatGen, an integrated database containing data from bioinformatic and patent resources. This effort addresses the inconsistency of publicly available genetic patent data coverage by providing access to a consolidated dataset. AVAILABILITY: PatGen can be searched at http://www.patgendb.com CONTACT: rjdrouse@patentinformatics.com.

Abstracting and Indexing↗
PubMed1997

Efficacy and tolerability of a topical NSAID patch (local action transcutaneous flurbiprofen) and oral diclofenac in the treatment of soft-tissue rheumatism.

The efficacy and safety of local action transcutaneous flurbiprofen 40 mg [flurbiprofen LAT] patches and diclofenac sodium tablets, 50 mg b.d., were compared in an open, multicentre, randomized, parallel-group study in patients with soft-tissue rheumatism. Patches were replaced at 12-hourly intervals. Clinical assessments were performed after 7 and 14 days of treatment. Fifty-six patients were treated with flurbiprofen LAT and 53 with diclofenac. Six withdrawals (three from each group) occurred during the treatment period. A statistically significant difference was observed in favour of flurbiprofen LAT for the principal measure, namely the investigator's opinion of overall change in clinical condition: 49/53 (92%) patients treated with flurbiprofen LAT had improved by day 14 compared with 36/49 (73%) patients receiving diclofenac sodium (p = 0.03; eligible dataset). There were also statistically significant differences in favour of flurbiprofen LAT for the investigator's assessments of the overall severity of the clinical condition (p = 0.03; eligible dataset), for the severity of pain at the region treated (p = 0.04; intent-to-treat), and for the severity of tenderness (p < 0.001; intent-to-treat). Supplementary analgesia (paracetamol) was required by two patients in the flurbiprofen LAT group and by eight diclofenac-treated patients. The difference in favour of flurbiprofen LAT in the average daily consumption of paracetamol was significant (p = 0.04). The patients' assessment of severity of pain on movement also favoured flurbiprofen LAT (p = 0.049; eligible dataset), but there were no statistically significant differences in day or night pain or quality of sleep. For the patients' opinion of treatment there was, however, a statistically significant difference in favour of flurbiprofen LAT (p = 0.02). Of the patients receiving flurbiprofen LAT, 94% regarded it as a convenient form of treatment. With respect to tolerability 8/56 (14%) patients applying flurbiprofen patches reported a total of nine adverse effects (AEs) (mainly local, mild skin irritations), vs 9/52 (17%) patients receiving diclofenac, who reported 12 AEs. Most AEs in the enteric-coated diclofenac group were of a gastrointestinal nature (one of which was severe). In terms of the proportion of patients reporting AEs related to the digestive system, there was a statistically significant difference in favour of flurbiprofen LAT (p = 0.011). In conclusion, local treatment of soft-tissue rheumatism with flurbiprofen LAT was demonstrably superior to benchmark oral therapy with diclofenac sodium over a 2-week period in terms of both efficacy and gastrointestinal tolerability. Flurbiprofen LAT provided both an effective and convenient form of topical SAID treatment.

Administration, Cutaneous↗
PubMed2003

Assimilating satellite ocean-colour observations into oceanic ecosystem models.

The effectiveness of ocean-colour data assimilation in providing robust biological-parameter estimates for basin-scale ecosystem models is investigated for a phytoplankton-zooplankton-nutrient model using North Atlantic satellite chlorophyll data. The model is forced by annual cycles of mixed-layer depth, day length, photosynthetically available radiation and a temperature-dependent phytoplankton maximum growth rate. Although ocean-colour data are potentially limited in their ability to constrain model parameters because they provide information about the phytoplankton component only, this limitation is offset by the volume of data available covering the range of possible biogeochemical responses to similar and widely varying physical conditions. The results are improved by applying wintertime nutrient estimates based on in situ observations as an additional constraint. Repeatability of parameter estimates obtained from independent samples is examined. Results obtained using regional and basin-wide sampling strategies for obtaining the optimization dataset are compared and the geographic applicability of the calibrated models is assessed.

Animals↗
PubMed2001

A simple method for statistical analysis of intensity differences in microarray-derived gene expression data.

BACKGROUND: Microarray experiments offer a potent solution to the problem of making and comparing large numbers of gene expression measurements either in different cell types or in the same cell type under different conditions. Inferences about the biological relevance of observed changes in expression depend on the statistical significance of the changes. In lieu of many replicates with which to determine accurate intensity means and variances, reliable estimates of statistical significance remain problematic. Without such estimates, overly conservative choices for significance must be enforced. RESULTS: A simple statistical method for estimating variances from microarray control data which does not require multiple replicates is presented. Comparison of datasets from two commercial entities using this difference-averaging method demonstrates that the standard deviation of the signal scales at a level intermediate between the signal intensity and its square root. Application of the method to a dataset related to the beta-catenin pathway yields a larger number of biologically reasonable genes whose expression is altered than the ratio method. CONCLUSIONS: The difference-averaging method enables determination of variances as a function of signal intensities by averaging over the entire dataset. The method also provides a platform-independent view of important statistical properties of microarray data.

Algorithms↗
PubMed1992

Cutoff assignment strategies for enhancing randomized clinical trials.

The randomized clinical trial (RCT) is the preferred method for assessing the efficacy of treatments. Recent ethical and logistical criticisms suggest that new variations of the traditional RCT are needed. Some of these criticisms may be addressed with new hybrid designs that combine random assignment with assignment by one or more cutoff values on a baseline variable (e.g., severity of illness). In a simple version of such a "cutoff-based" RTC, persons scoring below a cutoff score on a baseline measure (i.e., the least severely ill) are automatically assigned to the control-treated group, those scoring above a second, higher cutoff (i.e., the most ill) are automatically assigned to the test-treated group, and those scoring in the interval between the cutoff scores (i.e., the moderately ill) are randomly assigned to either group. Depending on the baseline score, the patient is assigned to treatment either randomly or by the need-based, clinically related baseline score. Six cutoff-based design variations are studied via simulations and compared with the traditional RCT and the single-cutoff (i.e., regression-discontinuity) design. All variations yield unbiased estimates of the treatment effect but estimates differ in efficiency, with the RCT being most efficient and the single-cutoff design being least efficient. Secondary analyses of data from the Cross-National Collaborative Study of the Effects of Alprazolam (Xanax) on panic are conducted for each variation by selectivity discarding cases from the original dataset to stimulate cutoff-based assignment. The results confirm the simulations and illustrate how cutoff-based designs might look with real data.

Alprazolam↗
PubMed2026

Precision Optimization of Behavioral Activation for Major and Subthreshold Depression: A Meta-Analysis of Exploring Dose-Response Relationships and Moderating Factors.

OBJECTIVE: This meta-analysis evaluated the efficacy of behavioral activation (BA) in adolescents with subthreshold depression (SD) or major depressive disorder (MDD), exploring dose-response relationships and moderating factors. METHOD: We searched PubMed, EMBASE, Web of Science, EBSCO, Scopus, and the Cochrane Library for randomized controlled trials (RCTs) through December 31, 2024. Risk of bias was assessed using RoB-2, and evidence quality with Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Analyses were performed with R, using standardized mean difference (SMD) for continuous variables and meta-regression for dose-response relationships. Subgroup analyses included symptom severity, intervention setting, delivery format, and parental involvement. The primary outcome was the reduction in depressive symptoms (PROSPERO: CRD42023444273). RESULTS: A total of 14 studies were included (11 RCTs meta-analyzed, comprising 572 participants). BA demonstrated a moderate effect size compared to treatment-as-usual (SMD = -0.42) and a large effect size compared to no-treatment controls (SMD = -0.87). BA was more effective for mild depressive symptoms (SMD = -0.93) than severe symptoms (SMD = -0.43), with significant efficacy in university settings (SMD = -0.94). Intervention without parental involvement exhibited significantly larger effects than those with parental participation (SMD = -0.94 vs -0.38; p < .0001), although this finding was likely confounded by age, symptom severity, and intervention setting. BA moderately improved both behavioral activation levels and functioning (SMD = 0.49). CONCLUSION: Short-term, school-based BA is significantly beneficial for older adolescents with mild depressive symptoms. Findings provide practical guidance for optimizing BA implementation and highlight directions for future research, including the need for larger sample sizes, standardized follow-up assessments, and more representative samples. PLAIN LANGUAGE SUMMARY: This meta-analysis evaluated the effectiveness of behavioral activation (BA), a therapeutic approach focused on improving positive activities, in adolescents with subthreshold depression or major depressive disorder. Based on 14 included studies and 572 participants, BA was found to be more effective for subthreshold compared to major depression. These findings suggest a promising role for BA as an early intervention tool in adolescent depression. STUDY REGISTRATION INFORMATION: Precision Optimization of Behavioral Activation for Major and Subthreshold Depression: A Meta-Analysis of Exploring Dose-response Relationships and Moderating Factors; https://www.crd.york.ac.uk/PROSPERO/view/CRD42023444273. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. Diverse cell lines and/or genomic datasets were not available. We actively worked to promote sex and gender balance in our author group.

Humans↗
PubMed2005

Evaluation of BioCreAtIvE assessment of task 2.

BACKGROUND: Molecular Biology accumulated substantial amounts of data concerning functions of genes and proteins. Information relating to functional descriptions is generally extracted manually from textual data and stored in biological databases to build up annotations for large collections of gene products. Those annotation databases are crucial for the interpretation of large scale analysis approaches using bioinformatics or experimental techniques. Due to the growing accumulation of functional descriptions in biomedical literature the need for text mining tools to facilitate the extraction of such annotations is urgent. In order to make text mining tools useable in real world scenarios, for instance to assist database curators during annotation of protein function, comparisons and evaluations of different approaches on full text articles are needed. RESULTS: The Critical Assessment for Information Extraction in Biology (BioCreAtIvE) contest consists of a community wide competition aiming to evaluate different strategies for text mining tools, as applied to biomedical literature. We report on task two which addressed the automatic extraction and assignment of Gene Ontology (GO) annotations of human proteins, using full text articles. The predictions of task 2 are based on triplets of protein--GO term--article passage. The annotation-relevant text passages were returned by the participants and evaluated by expert curators of the GO annotation (GOA) team at the European Institute of Bioinformatics (EBI). Each participant could submit up to three results for each sub-task comprising task 2. In total more than 15,000 individual results were provided by the participants. The curators evaluated in addition to the annotation itself, whether the protein and the GO term were correctly predicted and traceable through the submitted text fragment. CONCLUSION: Concepts provided by GO are currently the most extended set of terms used for annotating gene products, thus they were explored to assess how effectively text mining tools are able to extract those annotations automatically. Although the obtained results are promising, they are still far from reaching the required performance demanded by real world applications. Among the principal difficulties encountered to address the proposed task, were the complex nature of the GO terms and protein names (the large range of variants which are used to express proteins and especially GO terms in free text), and the lack of a standard training set. A range of very different strategies were used to tackle this task. The dataset generated in line with the BioCreative challenge is publicly available and will allow new possibilities for training information extraction methods in the domain of molecular biology.

Computational Biology↗
PubMed2004

The expression of aversion to medicines in general practice consultations.

Although the relevance of patients' views about medicines for their medicine taking behaviour is now well established, little is known about the ways in which these views are discussed in primary care consultations. In particular, many studies have demonstrated patients' aversion to medicines. This paper examines the form that aversion talk takes in the consultation and how doctors respond to patients' expression of aversion to medicines. It is based on a dataset of 35 case studies of general practice consultations in England. In interviews with researchers, aversion to medicines was expressed in 34 of the 35 cases. In consultations with doctors, aversion was expressed in 10 cases. The interactional dimension of aversion talk in consultations was analysed using Conversation Analysis, and two general patterns were identified. Aversion could be used as an interactional resource, or it could be a topic in its own right. If used as an interactional resource, no real discussion of patients' views of medicines took place. When aversion was a conversational topic in its own right, two situations were observed. Firstly, the doctor elicited patients' views directly. Secondly, patients initiated aversive talk using a range of indirect strategies to do so. Even when patients managed to express their aversion to medicines, doctors did not engage them in any real discussion of their views. A scheme of interpretation is suggested to explain these findings. In this scheme patients perceive medicines to be an extension of the doctor and to be beneficial. In this view it is right for doctors to prescribe medicines and for patients to take medicines. The results of this paper suggest that using aversion as an interactional resource might be the only safe way for patients to express their aversion without seeming to breach the social contract.

Adult↗
PubMed2002

An automatic microcalcification detection system based on a hybrid neural network classifier.

A hybrid intelligent system is presented for the identification of microcalcification clusters in digital mammograms. The proposed method is based on a three-step procedure: (a) preprocessing and segmentation, (b) regions of interest (ROI) specification, and (c) feature extraction and classification. The reduction of false positive cases is performed using an intelligent system containing two sub-systems: a rule-based and a neural network sub-system. In the first step of the classification schema 22 features are automatically computed which refer either to individual microcalcifications or to groups of them. Further reduction in the number of features is achieved through principal component analysis (PCA). The proposed methodology is tested using the Nijmegen and the Mammographic Image Analysis Society (MIAS) mammographic databases. Results are presented as the receiver operating characteristic (ROC) performance and are quantified by the area under the ROC curve (A(z)). In particular, the A(z) value for the Nijmegen dataset is 0.91 and for the MIAS is 0.92. The detection specificity of the two sets is 1.80 and 1.15 false positive clusters per image, at the sensitivity level higher than 0.90, respectively.

Automation↗
PubMed2005

Automatic assignment of absolute configuration from 1D NMR data.

[reaction: see text] Opposite enantiomers exhibit different NMR properties in the presence of an external common chiral element, and a chiral molecule exhibits different NMR properties in the presence of external enantiomeric chiral elements. Automatic prediction of such differences, and comparison with experimental values, leads to the assignment of the absolute configuration. Here two cases are reported, one using a dataset of 80 chiral secondary alcohols esterified with (R)-MTPA and the corresponding (1)H NMR chemical shifts and the other with 94 (13)C NMR chemical shifts of chiral secondary alcohols in two enantiomeric chiral solvents. For the first application, counterpropagation neural networks were trained to predict the sign of the difference between chemical shifts of opposite stereoisomers. The neural networks were trained to process the chirality code of the alcohol as the input, and to give the NMR property as the output. In the second application, similar neural networks were employed, but the property to predict was the difference of chemical shifts in the two enantiomeric solvents. For independent test sets of 20 objects, 100% correct predictions were obtained in both applications concerning the sign of the chemical shifts differences. Additionally, with the second dataset, the difference of chemical shifts in the two enantiomeric solvents was quantitatively predicted, yielding r(2) 0.936 for the test set between the predicted and experimental values.

Alcohols↗
PubMed1999

Meta-analysis of genome searches.

We have developed a method for meta-analysis of genome scans which allows systematic integration of data from published results. The Genome Search Meta-analysis method (GSMA) uses a non-parametric ranking method to identify genetic regions that show consistently increased sharing statistics or lod scores. The GSMA ranks genetic regions according to the lod score or p-value achieved in each scan. The summed rank across studies is compared to its probability distribution assuming ranks are randomly assigned. The GSMA can confirm evidence for regions highlighted in the original genome scans, and identify novel regions, which did not reach significance in any scan. In this paper, the GSMA was applied to four genome screens in multiple sclerosis and across 11 screens from autoimmune disorders. The GSMA is appropriate for studies with different family ascertainment, markers, and statistical analysis methods. The method increases the power to detect individual linkages in a clinically homogeneous dataset and has the potential to detect susceptibility loci in clinically distinct diseases which show involvement of common pathogenetic pathways.

Autoimmune Diseases↗
PubMed2003

Molecular features of adult mouse small intestinal epithelial progenitors.

The adult mouse small intestinal epithelium undergoes perpetual regeneration, fueled by a population of multipotential stem cells and oligopotential daughters located at the base of crypts of Lieberkühn. Although the morphologic features of small intestinal epithelial progenitors (SiEPs) are known, their molecular features are poorly defined. Previous impediments to purification and molecular characterization of SiEPs include lack of ex vivo clonigenic assays and the difficulty of physically retrieving them from their niche where they are interspersed between their numerous differentiated Paneth cell daughters. To overcome these obstacles, we used germ-free transgenic mice lacking Paneth cells to obtain a consolidated population of SiEPs with normal proliferative activity. These cells were harvested by laser capture microdissection. Functional genomics analysis identified 163 transcripts enriched in SiEPs compared with Paneth cell-dominated normal crypt base epithelium. The dataset was validated by (i) correlation with the organellar composition of SiEPs versus Paneth cells, (ii) similarities to databases generated from recent mouse hematopoietic and neural stem cell genome anatomy projects, and (iii) laser capture microdissectionreal-time quantitative RT-PCR studies of progenitor cell-containing populations retrieved from the small intestines, colons, and stomachs of conventionally raised mice. The SiEP profile has prominent representation of genes involved in c-myc signaling and in the processing, localization, and translation of mRNAs. This dataset, together with our recent analysis of gene expression in the gastric stem cell niche, discloses a set of molecular features shared by adult mouse gut epithelial progenitors.

Animals↗
PubMedDate not supplied

National Emergency Medical Services Information System (NEMSIS).

The absence of emergency medical services (EMS) patient care data has hindered development and evaluation of EMS systems. The National Highway Traffic Safety Administration (NHTSA), in cooperation with the Health Resources and Services Administration (HRSA), has provided funding to the National Association of State EMS Directors to develop a National EMS Information System (NEMSIS). NEMSIS is being designed to provide a uniform national EMS dataset, with standard terms, definitions, and values, as well as a national EMS database, with aggregated data from all states on a limited number of data elements. Forty-eight of the states, the District of Columbia, and three territories signed a memorandum of agreement documenting support for the NEMSIS project and expressing a desire for full implementation of the NEMSIS dataset. NHTSA has agreed to house the National EMS Database at its National Center for Statistics and Analysis. NHTSA, in cooperation with HRSA and the Centers for Disease Control and Prevention, recently entered into a cooperative agreement with the University of Utah School of Medicine to operate a NEMSIS Technical Assistance Center that will provide related assistance to official EMS agencies and to commercial software vendors. The Technical Assistance Center will also biannually assess state and territorial capabilities to provide data to the national EMS database. NEMSIS will provide a uniform national EMS dataset, with standard terms, definitions, and values, as well as a national EMS database, with aggregated data from all states on a limited number of data elements. Many of the potential benefits of implementation of NEMSIS are enumerated in this report.

Databases as Topic↗
PubMed2006

LdCompare: rapid computation of single- and multiple-marker r2 and genetic coverage.

UNLABELLED: The scale of genetic-variation datasets has increased enormously and the linkage equilibrium (LD) structure of these polymorphisms, particularly in whole-genome association studies, is of great interest. The significant computational complexity of calculating single- and multiple-marker correlations at a genome-wide scale remains challenging. We have developed a program that efficiently characterizes whole-genome LD structure on large number of SNPs in terms of single- and multiple-marker correlations. AVAILABILITY: LdCompare is licensed under the GNU General Public License (GPL). Source code, documentation, testing datasets and precompiled executables are available for download at: http://www.affymetrix.com/support/developer/tools/devnettools.affx

Algorithms↗
PubMed2001

A relationship between gene expression and protein interactions on the proteome scale: analysis of the bacteriophage T7 and the yeast Saccharomyces cerevisiae.

The relationship between the similarity of expression patterns for a pair of genes and interaction of the proteins they encode is demonstrated both for the simple genome of the bacteriophage T7 and the considerably more complex genome of the yeast Saccharomyces cerevisiae. Statistical analysis of large-scale gene expression and protein interaction data shows that protein pairs encoded by co-expressed genes interact with each other more frequently than with random proteins. Furthermore, the mean similarity of expression profiles is significantly higher for respective interacting protein pairs than for random ones. Such coupled analysis of gene expression and protein interaction data may allow evaluation of the results of large-scale gene expression and protein interaction screens as demonstrated for several publicly available datasets. The role of this link between expression and interaction in the evolution from monomeric to oligomeric protein structures is also discussed.

Bacteriophage T7↗