SEARCH · PubMed Health

Results for “Software development”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 631 records · Page 35Linked to original sources

PubMed2000

Case-based reasoning computer algorithm that uses mammographic findings for breast biopsy decisions.

OBJECTIVE: We present case-based reasoning computer software developed from mammographic findings to provide support for the clinical decision to perform biopsy of the breast. SUBJECTS AND METHODS: The case-based reasoning system is designed to support the decision to perform biopsy in those patients who have suspicious findings on diagnostic mammography. Currently, between 66% and 90% of biopsies are performed on benign lesions. Our system is designed to help decrease the number of benign biopsies without missing malignancies. Clinicians interpret the mammograms using a standard reporting lexicon. The case-based reasoning system compares these findings with a database of cases with known outcomes (from biopsy) and returns the fraction of similar cases that were malignant. This malignancy fraction is an intuitive response that the clinician can then consider when making the decision regarding biopsy. RESULTS: The system was evaluated using a round-robin sampling scheme and performed with an area under the receiver operating characteristic curve of 0.83, comparable with the performance of a neural network model. If only the cases returning a malignancy fraction of greater than a threshold of 0.10 are sent to biopsy, no malignancies would be missed, and the number of benign biopsies would be decreased by 25%. At a threshold of 0.21, 98%, of the malignancies would be biopsied, and the number of benign biopsies would be decreased by 41%. CONCLUSION: This preliminary investigation indicates that the case-based reasoning approach to computer-aided diagnosis has the potential to improve the accuracy of breast cancer diagnosis on mammography.

Adult↗

PubMed2005

The "dashpot" mechanism of stretch-dependent gating in MscS.

The crystal structure of the small conductance mechanosensitive channel (MscS) has been an invaluable tool in the search for the gating mechanism, however many functional aspects of the channel remain unsettled. Here we characterized the gating of MscS in Escherichia coli spheroplasts in a triple mutant (mscL-, mscS-, mscK-) background. We used a pressure clamp apparatus along with software developed in-lab to generate dose-response curves directly from two-channel recordings of current and pressure. In contrast to previous publications, we found that MscS exhibits essentially voltage-independent activation by tension, but at the same time strong voltage-dependent inactivation under depolarizing conditions. The MscS activation curves obtained under saturating ramps of pressure, at different voltages, gave estimates for the energy, area, and gating charge for the closed-to-open transition as 24 kT, 18 nm2, and +0.8, respectively. The character of activation and inactivation was similar in both K+ and Na+ buffers. Perhaps the most salient and intriguing property of MscS gating was a strong dependence on the rate of pressure application. Patches subjected to various pressure ramps from 2.7 to 240 mmHg/s revealed a midpoint of activation almost independent of rate. However, the resultant channel activity was dramatically lower when pressure was applied slowly, especially at depolarizing pipette voltages. It appears that MscS prefers to respond in full to abrupt stimuli but manages to ignore those applied slowly, as if the gate were connected to the tension-transmitting element via a velocity-sensitive "dashpot." With slower ramps, channels inactivate during the passage through a narrow region of pressures below the activation midpoint. This property of "dumping" a slowly applied force may be important in environmental situations where rehydration of cells occurs gradually and release of osmolytes is not desirable. MscS often enters the inactivated state through subconducting states favored by depolarizing voltage. The inactivation rate increases exponentially with depolarization. Based on these results we propose a kinetic scheme and gating mechanism to account for the observed phenomenology in the framework of available structural information.

Electrophysiology↗

PubMed2005

Comparison of label-free methods for quantifying human proteins by shotgun proteomics.

Measurements of mass spectral peak intensities and spectral counts are promising methods for quantifying protein abundance changes in shotgun proteomic analyses. We describe Serac, software developed to evaluate the ability of each method to quantify relative changes in protein abundance. Dynamic range and linearity using a three-dimensional ion trap were tested using standard proteins spiked into a complex sample. Linearity and good agreement between observed versus expected protein ratios were obtained after normalization and background subtraction of peak area intensity measurements and correction of spectral counts to eliminate discontinuity in ratio estimates. Peak intensity values useful for protein quantitation ranged from 10(7) to 10(11) counts with no obvious saturation effect, and proteins in replicate samples showed variations of less than 2-fold within the 95% range (+/-2sigma) when >or=3 peptides/protein were shared between samples. Protein ratios were determined with high confidence from spectral counts when maximum spectral counts were >or=4 spectra/protein, and replicates showed equivalent measurements well within 95% confidence limits. In further tests, complex samples were separated by gel exclusion chromatography, quantifying changes in protein abundance between different fractions. Linear behavior of peak area intensity measurements was obtained for peptides from proteins in different fractions. Protein ratios determined by spectral counting agreed well with those determined from peak area intensity measurements, and both agreed with independent measurements based on gel staining intensities. Overall spectral counting proved to be a more sensitive method for detecting proteins that undergo changes in abundance, whereas peak area intensity measurements yielded more accurate estimates of protein ratios. Finally these methods were used to analyze differential changes in protein expression in human erythroleukemia K562 cells stimulated under conditions that promote cell differentiation by mitogen-activated protein kinase pathway activation. Protein changes identified with p<0.1 showed good correlations with parallel measurements of changes in mRNA expression.

Bias↗

PubMed1998

Effects of computer-based clinical decision support systems on physician performance and patient outcomes: a systematic review.

CONTEXT: Many computer software developers and vendors claim that their systems can directly improve clinical decisions. As for other health care interventions, such claims should be based on careful trials that assess their effects on clinical performance and, preferably, patient outcomes. OBJECTIVE: To systematically review controlled clinical trials assessing the effects of computer-based clinical decision support systems (CDSSs) on physician performance and patient outcomes. DATA SOURCES: We updated earlier reviews covering 1974 to 1992 by searching the MEDLINE, EMBASE, INSPEC, SCISEARCH, and the Cochrane Library bibliographic databases from 1992 to March 1998. Reference lists and conference proceedings were reviewed and evaluators of CDSSs were contacted. STUDY SELECTION: Studies were included if they involved the use of a CDSS in a clinical setting by a health care practitioner and assessed the effects of the system prospectively with a concurrent control. DATA EXTRACTION: The validity of each relevant study (scored from 0-10) was evaluated in duplicate. Data on setting, subjects, computer systems, and outcomes were abstracted and a power analysis was done on studies with negative findings. DATA SYNTHESIS: A total of 68 controlled trials met our criteria, 40 of which were published since 1992. Quality scores ranged from 2 to 10, with more recent trials rating higher (mean, 7.7) than earlier studies (mean, 6.4) (P<.001). Effects on physician performance were assessed in 65 studies and 43 found a benefit (66%). These included 9 of 15 studies on drug dosing systems, 1 of 5 studies on diagnostic aids, 14 of 19 preventive care systems, and 19 of 26 studies evaluating CDSSs for other medical care. Six of 14 studies assessing patient outcomes found a benefit. Of the remaining 8 studies, only 3 had a power of greater than 80% to detect a clinically important effect. CONCLUSIONS: Published studies of CDSSs are increasing rapidly, and their quality is improving. The CDSSs can enhance clinical performance for drug dosing, preventive care, and other aspects of medical care, but not convincingly for diagnosis. The effects of CDSSs on patient outcomes have been insufficiently studied.

Clinical Competence↗

PubMed2004

HICOPS: human interface computer program in space.

BACKGROUND: During long experimental set ups, a protocol book usually guides cosmonauts. This is not very easy to work with in microgravity conditions and is not very efficient. For the cardiovascular physiology experiment CARDIOCOG during the Belgian Soyuz Mission (Odissea, November 2002) we developed a software program that guided the cosmonauts through the experiment. The software was developed in LabVIEW, thoroughly tested by CNES and the Russian space authorities and transported to the ISS as a stand-alone application. An adapted version was used during the Spanish Cervantes Mission in October 2003. RESULTS: This program provided several advantages: (1) error procedures could be easily dealt with in using the program's incorporated error structure; (2) the experimental sequences were easy to follow for the cosmonauts; (3) the experimental duration was exactly the same for all repetitions of the experiment, since the program imposed the timing; (4) after the flight, we were able to reconstruct all sequences of the experiment using a log-file that was automatically created during the different steps of the experiment; and (5) we were able to impose exact breathing frequencies to the cosmonauts using a visual aid. CONCLUSION: Less training was necessary for the cosmonauts to learn the experiment. Reconstruction of the experiment timing was easy. Exact breathing frequencies were obtained at each repetition. The program HICOPS worked to the overall satisfaction of the cosmonauts and they preferred working with HICOPS instead of with paper flow sheets. Data for the cardiovascular experiment during both missions were obtained in a standardised way.

Aerospace Medicine↗

PubMed2004

Move over ANOVA: progress in analyzing repeated-measures data and its reflection in papers published in the Archives of General Psychiatry.

BACKGROUND: The analysis of repeated-measures data presents challenges to investigators and is a topic for ongoing discussion in the Archives of General Psychiatry. Traditional methods of statistical analysis (end-point analysis and univariate and multivariate repeated-measures analysis of variance [rANOVA and rMANOVA, respectively]) have known disadvantages. More sophisticated mixed-effects models provide flexibility, and recently developed software makes them available to researchers. OBJECTIVES: To review methods for repeated-measures analysis and discuss advantages and potential misuses of mixed-effects models. Also, to assess the extent of the shift from traditional to mixed-effects approaches in published reports in the Archives of General Psychiatry. DATA SOURCES: The Archives of General Psychiatry from 1989 through 2001, and the Department of Veterans Affairs Cooperative Study 425. STUDY SELECTION: Studies with a repeated-measures design, at least 2 groups, and a continuous response variable. DATA EXTRACTION: The first author ranked the studies according to the most advanced statistical method used in the following order: mixed-effects model, rMANOVA, rANOVA, and end-point analysis. DATA SYNTHESIS: The use of mixed-effects models has substantially increased during the last 10 years. In 2001, 30% of clinical trials reported in the Archives of General Psychiatry used mixed-effects analysis. CONCLUSIONS: Repeated-measures ANOVAs continue to be used widely for the analysis of repeated-measures data, despite risks to interpretation. Mixed-effects models use all available data, can properly account for correlation between repeated measurements on the same subject, have greater flexibility to model time effects, and can handle missing data more appropriately. Their flexibility makes them the preferred choice for the analysis of repeated-measures data.

Analysis of Variance↗

PubMed1998

Extending the simple linear regression model to account for correlated responses: an introduction to generalized estimating equations and multi-level mixed modelling.

Much of the research in epidemiology and clinical science is based upon longitudinal designs which involve repeated measurements of a variable of interest in each of a series of individuals. Such designs can be very powerful, both statistically and scientifically, because they enable one to study changes within individual subjects over time or under varied conditions. However, this power arises because the repeated measurements tend to be correlated with one another, and this must be taken into proper account at the time of analysis or misleading conclusions may result. Recent advances in statistical theory and in software development mean that studies based upon such designs can now be analysed more easily, in a valid yet flexible manner, using a variety of approaches which include the use of generalized estimating equations, and mixed models which incorporate random effects. This paper provides a particularly simple illustration of the use of these two approaches, taking as a practical example the analysis of a study which examined the response of portable peak expiratory flow meters to changes in true peak expiratory flow in 12 children with asthma. The paper takes the reader through the relevant practicalities of model fitting, interpretation and criticism and demonstrates that, in a simple case such as this, analyses based upon these model-based approaches produce reassuringly similar inferences to standard analyses based upon more conventional methods.

Adolescent↗

PubMed1999

In vitro motility evaluation of aggregated cancer cells by means of automatic image processing.

BACKGROUND: Set up of an automatic image processing based method that enables the motility of in vitro aggregated cells to be evaluated for a number of hours. METHODS: Our biological model included the PC-3 human prostate cancer cell line growing as a monolayer on the bottom of Falcon plastic dishes containing conventional culture media. Our equipment consisted of an incubator, an inverted phase contrast microscope, a Charge Coupled Device (CCD) video camera, and a computer equipped with an image processing software developed in our laboratory. This computer-assisted microscope analysis of aggregated cells enables global cluster motility to be evaluated. This analysis also enables the trajectory of each cell to be isolated and parametrized within a given cluster or, indeed, the trajectories of individual cells outside a cluster. RESULTS: The results show that motility inside a PC-3 cluster is not restricted to slight motion due to cluster expansion, but rather consists of a marked cell movement within the cluster. CONCLUSIONS: The proposed equipment enables in vitro aggregated cell motility to be studied. This method can, therefore, be used in pharmacological studies in order to select anti-motility related compounds. The compounds selected by the equipment described could then be tested in vivo as potential anti-metastatic.

Algorithms↗

PubMed2001

Combined confocal and wide-field high-resolution cytometry of fluorescent in situ hybridization-stained cells.

BACKGROUND: The recently developed technique of high-resolution cytometry (HRCM) enables automated acquisition and analysis of fluorescent in situ hybridization (FISH)-stained cell nuclei using conventional wide-field fluorescence microscopy. The method has now been extended to confocal imaging and offers the opportunity to combine the advantages of confocal and wide-field modes. METHODS: We have automated image acquisition and analysis from a standard inverted fluorescence microscope equipped with a confocal module with Nipkow disk and a cooled digital CCD camera. The system is fully controlled by a high-performance computer that performs both acquisition and related on-line image analysis. The system can be used either for an automatic two (2D) and three-dimensional (3D) analysis of FISH- stained interphase nuclei or for a semiautomatic 3D analysis of FISH-stained cells in tissues. The user can select which fluorochromes are acquired using wide-field mode and which using confocal mode. The wide-field and confocal images are overlaid automatically in computer memory. The developed software compensates automatically for both chromatic color shifts and spatial shifts caused by switching to a different imaging mode. RESULTS: Using the combined confocal and wide-field HRCM technique, it is possible to take advantage of both imaging modes. Images of some dyes (such as small hybridization dots or counterstain images of individual interphase nuclei) do not require confocal quality and can be acquired quickly in wide-field mode. On the contrary, images of other dyes (such as chromosome territories or counterstain images of cells in tissues) do require improved quality and are acquired in confocal mode. The dual-mode approach is two to three times faster compared with the single-mode confocal approach and the spectrum of its applications is much broader compared with both single-mode confocal and single-mode wide-field systems. CONCLUSIONS: The combination of high speed specific to the wide-field mode and high quality specific to the confocal mode gives optimal system performance.

Cell Nucleus↗

PubMed2003

Steroids for improving recovery following tonsillectomy in children.

BACKGROUND: Tonsillectomy continues to be one of the most common surgical procedures performed worldwide. Despite advances in anesthetic and surgical techniques, post-tonsillectomy morbidity remains a significant clinical problem. OBJECTIVES: To assess the clinical efficacy of a single intra-operative dose of dexamethasone in reducing post-tonsillectomy morbidity. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (Issue 1, 2002), MEDLINE (from 1966 - February 2002), EMBASE (from 1974 - February 2002) and reference lists of relevant articles. We contacted leading experts for information on any relevant unpublished data. SELECTION CRITERIA: Randomized, double-blind, placebo-controlled trials of a single dose of intravenous, intra-operative corticosteroid for pediatric patients (age < 18 years) who underwent tonsillectomy or adenotonsillectomy were included. DATA COLLECTION AND ANALYSIS: Data regarding the primary outcome measures and measurement tools were extracted by the first author from the published studies. Data regarding study design, patient ages, procedures performed, dose of corticosteroid and method of delivery, as well as methodologic quality were also recorded by the first author. When data were missing from the original publications, the authors were contacted for more information. Data analysis was performed with a random effects model, using the RevMan 4.1 software developed by the Cochrane Collaboration. MAIN RESULTS: Children receiving a single intra-operative dose of dexamethasone (dose range = 0.15 to 1.0 mg/kg; maximum dose range = 8 to 25 mg) were two times less likely to vomit in the first 24 hours than children receiving placebo (RR = 0.54, CI95 = 0.42, 0.69; p < 0.00001). Routine use in four children would be expected to result in one less patient experiencing post-tonsillectomy emesis (RD = -0.25, CI95 = -0.37, -0.13; p = 0.00004). Additionally, children receiving dexamethasone were more likely to advance to a soft/solid diet on post-tonsillectomy day 1 (RR = 1.69, CI95 = 1.02, 2.79; p = 0.04) than those receiving placebo. Due to missing data and varied outcome measurement tools, pain could not be meaningfully analyzed as a distinct outcome measure. REVIEWER'S CONCLUSIONS: The evidence suggests that a single intravenous dose of dexamethasone is an effective, relatively safe and inexpensive treatment for reducing morbidity from pediatric tonsillectomy. No adverse events attributable to dexamethasone were reported in these trials. Additionally, in our 10-year experience of routine use of a single intravenous dose of dexamethasone during pediatric tonsillectomy, there have been no attributable, adverse events. Lastly, we found no reports in the literature of complications from use of a single intravenous dose of corticosteroid during pediatric tonsillectomy.

Adenoidectomy↗

PubMed2002

Fourier-transform mass spectrometry for automated fragmentation and identification of 5-20 kDa proteins in mixtures.

When presented with a mixture of intact proteins, electrospray ionization with Fourier-transform mass spectrometry (ESI-FTMS) has the capability to obtain direct fragmentation information from isolated ions. However, the automation of this capability has not been achieved to date. We have developed software for unattended acquisition of protein tandem mass spectrometry (MS/MS) data and batch processing of the resulting files for identification of whole proteins. Mixtures of both protein standards (8-29 kDa) and Methanococcus jannaschii cytosolic proteins (up to six components + 20 kDa) were infused via an autosampler, and MS/MS data were acquired without human intervention. The acquisition software recognizes ESI charge state patterns, generates protein-specific isolation waveforms on-the-fly, and fragments ions using two different infrared laser times. In addition to protein standards, five wild-type proteins (7-14 kDa) were identified automatically with 100% sequence coverage from the M. jannaschii database. The software underpins a measurement platform for sample-dependent acquisition of MS/MS data for whole proteins, a critical step to realize proteomics with 100% sequence coverage in a higher throughput setting.

Archaeal Proteins↗

PubMed2005

Australopithecus anamensis: a finite-element approach to studying the functional adaptations of extinct hominins.

Australopithecus anamensis is the stem species of all later hominins and exhibits the suite of characters traditionally associated with hominins, i.e., bipedal locomotion when on the ground, canine reduction, and thick-enameled teeth. The functional consequences of its thick enamel are, however, unclear. Without appropriate structural reinforcement, these thick-enameled teeth may be prone to failure. This article investigates the mechanical behavior of A. anamensis enamel and represents the first in a series that will attempt to determine the functional adaptations of hominin teeth. First, the microstructural arrangement of enamel prisms in A. anamensis teeth was reconstructed using recently developed software and was compared with that of extant hominoids. Second, a finite-element model of a block of enamel containing one cycle of prism deviation was reconstructed for Homo, Pan, Gorilla, and A. anamensis and the behavior of these tissues under compressive stress was determined. Despite similarities in enamel microstructure between A. anamensis and the African great apes, the structural arrangement of prismatic enamel in A. anamensis appears to be more effective in load dissipation under these compressive loads. The findings may imply that this hominin species was well adapted to puncture crushing and are in some respects contrary to expectations based on macromorphology of teeth. Taking together, information obtained from both finite-element analyses and dental macroanatomy leads us to suggest that A. anamensis was probably adapted for habitually consuming a hard-tough diet. However, additional tests are needed to understand the functional adaptations of A. anamensis teeth fully.

Adaptation, Physiological↗

PubMedDate not supplied

Conformational studies of cyclic peptide structures in solution from 1H-Nmr data by distance geometry calculation and restrained energy minimization.

The three-dimensional structure of a cyclic bouvardin analogue, cyclo (-Pro-MeTyr-Ala-MeTyr-MeTyr-D-Ala-) has been determined by distance geometry calculation and restrained energy minimization from nmr data. The preparation of the input for the distance geometry calculations, the modification of the amino acid library, and the analysis of the structures were done with the aid of a recently developed software package, GEOM. A great variety of different initial structures were explored to check the uniqueness of the determined solution structure. Calculations with 500 different initial structures and two different strategies led to a uniquely determined backbone conformation with a root mean square deviations value of 0.4 A. The backbone structure consists of two beta-turns, a beta-II turn at Pro1-MeTyr2, and a beta-VI turn at MeTyr4-MeTyr5. The efficiency of the two calculation strategies were compared in order to propose an optimal means for performing distance geometry calculations with cyclic structures.

Amino Acid Sequence↗

PubMed1995

Image analysis in comparative genomic hybridization.

Comparative genomic hybridization (CGH) is a new technique by which genomic imbalances can be detected by combining in situ suppression hybridization of whole genomic DNA and image analysis. We have developed software for rapid, quantitative CGH image analysis by a modification and extension of the standard software used for routine karyotyping of G-banded metaphase spreads in the Magiscan chromosome analysis system. The DAPI-counterstained metaphase spread is karyotyped interactively. Corrections for image shifts between the DAPI, FITC, and TRITC images are done manually by moving the three images relative to each other. The fluorescence background is subtracted. A mean filter is applied to smooth the FITC and TRITC images before the fluorescence ratio between the individual FITC- and TRITC-stained chromosomes is computed pixel by pixel inside the area of the chromosomes determined by the DAPI boundaries. Fluorescence intensity ratio profiles are generated, and peaks and valleys indicating possible gains and losses of test DNA are marked if they exceed ratios below 0.75 and above 1.25. By combining the analysis of several metaphase spreads, consistent findings of gains and losses in all or almost all spreads indicate chromosomal imbalance. Chromosomal imbalances are detected either by visual inspection of fluorescence ratio (FR) profiles or by a statistical approach that compares FR measurements of the individual case with measurements of normal chromosomes. The complete analysis of one metaphase can be carried out in approximately 10 minutes.

Humans↗

PubMed1998

Genotyping of forensic short tandem repeat (STR) systems based on sizing precision in a capillary electrophoresis instrument.

Automated fluorescence analysis of polymerase chain reaction (PCR)-amplified short tandem repeat (STR) systems by capillary electrophoresis (CE) is becoming an established tool both in forensic casework and in the implementation of both state and national convicted offender DNA databases. A new capillary electrophoresis instrument, the ABI Prism 310 Genetic Analyzer, along with the Performance Optimized Polymer 4 (POP-4) provides an automated and precise method for simultaneously analyzing ten fluorescently labeled STR loci from a single PCR amplification kit, which provides a power of discrimination of approximately one in five billion from a single PCR amplification. Data are presented on sizing precision, sizing accuracy, and resolution for the STR loci in the AmpFlSTR Profiler kit. Sizing accuracy is highly dependent on the electrophoresis system, and therefore the reporting of alleles based on the nucleotide size obtained from an electrophoresis system is not recommended for forensic work. The precision of the 310 capillary electrophoresis system, coupled with software developed for automated genotyping of alleles based on the use of an allelic ladder, allows for accurate genotyping of STR loci. Sizing precision of < or = 0.16 nucleotide standard deviation was obtained with this system, thus allowing for accurate genotyping of length variants that differ in length by a single nucleotide.

Alleles↗

PubMed2005

Automatic analysis of multiplex ligation-dependent probe amplification products (exemplified by a commercial kit for prenatal aneuploidy detection).

For use in routine prenatal diagnostics, we developed software and methods for automatic aneuploidy detection based on a commercial multiplex ligation-dependent probe amplification (MLPA) kit. Software and methods ensure a reliable, objective, and fast workflow, and may be applied to other types of MLPA kits. Following CE of MLPA amplification products, the software automatically identified the peak area for each probe, normalized it in relation to the neighboring peak areas of the test sample, computed the ratio relative to a reference created from normal samples, and compensated the ratio for a side effect of the normalization procedure that scaled all chromosomally normal DNA peak areas slightly up or down depending on the kind of aneuploidy present. For the chromosomes 13, 18, 21, X, and Y, probe reliability weighted mean ratio values and corresponding SDs were calculated, and the significance for being outside a reference interval around ratio 1.0 was tested. p < or = 1% suggested aneuploidy and 1 < p < or = 5% suggested potential aneuploidy. Individual peaks, where the normalized area was situated more than 4 SD from the corresponding reference, suggested possible partial deletion or gain. Sample quality was automatically assessed. Control probes were not required. Having used the software and methods for two years, we conclude that a reliable, objective, and fast workflow is obtained.

Aneuploidy↗

PubMed2005

Heterogeneity testing in meta-analysis of genome searches.

Genome searches for identifying susceptibility loci for the same complex disease often give inconclusive or inconsistent results. Genome Search Meta-analysis (GSMA) is an established non-parametric method to identify genetic regions that rank high on average in terms of linkage statistics (e.g., lod scores) across studies. Meta-analysis typically aims not only to obtain average estimates, but also to quantify heterogeneity. However, heterogeneity testing between studies included in GSMA has not been developed yet. Heterogeneity may be produced by differences in study designs, study populations, and chance, and the extent of heterogeneity might influence the conclusions of a meta-analysis. Here, we propose and explore metrics that indicate the extent of heterogeneity for specific loci in GSMA based on Monte Carlo permutation tests. We have also developed software that performs both the GSMA and the heterogeneity testing. To illustrate the concept, the proposed methodology was applied to published data from meta-analyses of rheumatoid arthritis (4 scans) and schizophrenia (20 scans). In the first meta-analysis, we identified 11 bins with statistically low heterogeneity and 8 with statistically high heterogeneity. The respective numbers were 9 and 6 for the schizophrenia meta-analysis. For rheumatoid arthritis, bins 6.2 (the HLA region that is a well-documented susceptibility locus for the disease) and 16.3 (16q12.2-q23.1) had both high average ranks and low between-study heterogeneity. For schizophrenia, this was seen for bin 3.2 (3p25.3-p22.1) and heterogeneity was still significantly low after adjusting for its high average rank. Concordance was high between the proposed metrics and between weighted and unweighted analyses. Data from genome searches should be synthesized and interpreted considering both average ranks and heterogeneity between studies.

Arthritis, Rheumatoid↗

PubMed1982

Effect of elicitation on peritoneal macrophage subpopulations: size distributions, ectoenzyme phenotypes and antitumor activity.

Resident (R), Brewer's thioglycollate broth (TG) and C. parvum (CP)-elicited murine peritoneal cell populations were separated into subpopulations by centrifugation on discontinuous Ficoll gradients consisting of layers of 4, 6, 8 and 10% Ficoll. The resulting subpopulations were shown to be distinct on the basis of cell size, ectoenzyme phenotypes and antitumor activity. The cell size distributions were analyzed by means of a Coulter channelyzer and software developed for a computer. The 4-6% Ficoll interface fraction comprised the smallest macrophages, with most cells in this subpopulation appearing to range in cell volume from 150-275 microns 3. The largest sized macrophages were found in the 10%-pellet fraction, with most cells appearing to range in cell volume from 300-600 microns 3. The ectoenzyme phenotypes of the R, TG and CP unseparated macrophage populations were significantly different. Moreover, the ectoenzyme phenotypes of the smallest, (4-6% Ficoll interface) subpopulation in the R and CP macrophages differed from the other subpopulations. Reduction in alkaline phosphodiesterase 1 (APD-1) ectoenzyme activity (as compared with unseparated R macrophages) appeared to be a marker for acquisition of antitumor activity. The small CP macrophages (4-6% Ficoll interface) showed no antitumor activity while the unseparated CP macrophages and all other CP macrophages subpopulations exhibited antitumor activity. The CP macrophage unseparated population and the subpopulations with antitumor activity expressed reduced ADP-1 activity. Conversely, the R or TG macrophage unseparated populations and their subpopulations, along with the CP macrophage 4-6% subpopulation, lacked antitumor activity and failed to show a change in ADP-1 ectoenzyme activity.

Animals↗