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PubMed2006

Combined permutation test and mixed-effect model for group average analysis in fMRI.

In group average analyses, we generalize the classical one-sample t test to account for heterogeneous within-subject uncertainties associated with the estimated effects. Our test statistic is defined as the maximum likelihood ratio corresponding to a Gaussian mixed-effect model. The test's significance level is calibrated using the same sign permutation framework as in Holmes et al., allowing for exact specificity control under a mild symmetry assumption about the subjects' distribution. Because our likelihood ratio test does not rely on homoscedasticity, it is potentially more sensitive than both the standard t test and its permutation-based version. We present results from the Functional Imaging Analysis Contest 2005 dataset to support this claim.

Algorithms↗

PubMed2006

Permutation testing of orthogonal factorial effects in a language-processing experiment using fMRI.

The block-paradigm of the Functional Image Analysis Contest (FIAC) dataset was analysed with the Brain Activation and Morphological Mapping software. Permutation methods in the wavelet domain were used for inference on cluster-based test statistics of orthogonal contrasts relevant to the factorial design of the study, namely: the average response across all active blocks, the main effect of speaker, the main effect of sentence, and the interaction between sentence and speaker. Extensive activation was seen with all these contrasts. In particular, different vs. same-speaker blocks produced elevated activation in bilateral regions of the superior temporal lobe and repetition suppression for linguistic materials (same vs. different-sentence blocks) in left inferior frontal regions. These are regions previously reported in the literature. Additional regions were detected in this study, perhaps due to the enhanced sensitivity of the methodology. Within-block sentence suppression was tested post-hoc by regression of an exponential decay model onto the extracted time series from the left inferior frontal gyrus, but no strong evidence of such an effect was found. The significance levels set for the activation maps are P-values at which we expect <1 false-positive cluster per image. Nominal type I error control was verified by empirical testing of a test statistic corresponding to a randomly ordered design matrix. The small size of the BOLD effect necessitates sensitive methods of detection of brain activation. Permutation methods permit the necessary flexibility to develop novel test statistics to meet this challenge.

Algorithms↗

PubMed2006

Motivation and synthesis of the FIAC experiment: Reproducibility of fMRI results across expert analyses.

The Functional Imaging Analysis Contest (FIAC) culminated in the FIAC Workshop held at the 11th Annual Meeting of the Organization for Human Brain Mapping in Toronto in 2005. This special issue summarizes various analyses used by contestants with a single functional magnetic resonance imaging (fMRI) study, a cortical-language study using sentence repetition. The results from the cognitive neuroscientists who developed the test-base language study, and report their data analysis, are complemented by expert analyses of the same test-base data by most of the major groups actively developing fMRI software packages. Analyses include many variants of the general linear model (GLM), cutting-edge spatial- and temporal-wavelets, permutation-based, and ICA approaches. A number of authors also include surface-based approaches. Several articles describe the important emerging areas of diagnostics for GLM analysis, multivariate predictive modeling, and functional connectivity analysis. While the FIAC did not achieve all of its goals, it helped identify new activation regions in the test-base data, and more important, through this special issue it illustrates the significant methods-driven variability that potentially exists in the literature. Variable results from different methods reported here should provide a cautionary note and motivate the Human Brain Mapping community to explore more thoroughly the methodologies they use for analyzing fMRI data.

Brain Mapping↗

PubMed2004

DFold: PCR design that minimizes secondary structure and optimizes downstream genotyping applications.

Secondary structures in polymerase chain reaction (PCR) target sequences have a negative impact on amplification success rates and on downstream uses of PCR products. For example, signal strength and allele discrimination in single nucleotide polymorphism (SNP) genotyping methods can be compromised by allele-biased amplification and/or by PCR product folding that limits access of interrogating probes. To increase the fidelity and robustness of PCR, and to aid follow-on applications, we have developed DFold (http://dfold.cgb.ki.se)-a generalized software solution that creates PCR oligonucleotide primer designs devoid of stable secondary structures. We demonstrate the effectiveness of the tool by applying it to a range of dynamic allele-specific hybridization (DASH) assay designs, many of which we evaluate in the laboratory. We further consider how the system throughput may be made sufficiently high for use upon millions of target sequences in order to support whole-genome analyses.

Algorithms↗

PubMed2005

Automated splicing mutation analysis by information theory.

Information theory-based software tools have been useful in interpreting noncoding sequence variation within functional sequence elements such as splice sites. Individual information analysis detects activated cryptic splice sites and associated splicing regulatory sites and is capable of distinguishing null from partially functional alleles. We present a server (https://splice.cmh.edu) designed to analyze splicing mutations in binding sites in either human genes, genome-mapped mRNAs, user-defined sequences, or dbSNP entries. Standard HUGO-approved gene symbols and HGVS-approved systematic mutation nomenclature (or dbSNP format) are entered via a web portal. After verifying the accuracy of input variant(s), the surrounding interval is retrieved from the human genome or user-supplied reference sequence. The server then computes the information contents (Ri) of all potential constitutive and/or regulatory splice sites in both the reference and variant sequences. Changes in information content are color-coded, tabulated, and visualized as sequence walkers, which display the binding sites with the reference sequence. The software was validated by analyzing approximately 1,300 mutations from Human Mutation as well as eight mapped SNPs from dbSNP designated as splice site variants. All of the splicing mutations and variants affected splice site strength or activated cryptic splice sites. The server also detected several missense mutations that were unexpectedly predicted to have concomitant effects on splicing or appeared to activate cryptic splicing.

Automation↗

PubMedDate not supplied

Computer-assisted identification and quantification of multiple sclerosis lesions in MR imaging volumes in the brain.

Magnetic resonance (MR) imaging is the principal imaging technique for the diagnosis of multiple sclerosis (MS). However, quantifying the number and extent of lesions on MR images manually is arduous. The authors have developed a computerized three-dimensional (3D) quantitative system to assist in the identification and analysis of MS lesions in proton-density (PD)- and T2-weighted volumes of the head. The system provides intuitive, interactive operations that allow flexible extraction of information from the data. Use of the system to analyze MR examinations of a phantom containing regular "lesions" showed that accurate (average error, < 0.21 cm3) and precise (10% or better for lesions > 1 cm3) measurements of objects less than 7 cm3 is possible, and that an estimate of the quantization error predicted the uncertainty in the volume. Analysis of four MR examinations of a chronic-progressive MS patient conducted over an 18-month period was performed. A two-dimensional histogram showing the frequency of voxels with particular PD- and T2-weighted intensities revealed a distinct cluster only in histograms of sections that contained lesions. Measurements and 3D volume rendering of lesions clearly showed changes in lesion shape, position, and size.

Algorithms↗

PubMed2006

Optimized clinical T2 relaxometry with a standard CPMG sequence.

PURPOSE: To optimize the accuracy and precision of T2 measurements using the standard Carr-Purcell-Meiboom-Gill (CPMG) sequence. T2 values obtained with this technique are normally sensitive to imperfect refocusing due to the formation of unwanted stimulated echoes. MATERIALS AND METHODS: Modifications are made to the refocusing slice selection width and the interleaving scheme. A widened refocusing slice improves the uniformity of the refocusing flip angle across the slice. A slow spin echo acquisition provided "gold standard" T2 values. Repeated T2 measurements in phantom and human studies are used to compare the accuracy and precision of the optimized and non-optimized CPMG implementations. RESULTS: The required slice thickness ratio between refocusing and excitation slice widths is found to be 3:1 for typical optimized radiofrequency pulses. T2 values obtained using this optimized implementation more closely correspond to "gold standard" values. Repeated T2 measurements indicate significantly improved correspondence between data and model. A reduction in the fitting error of approximately 70% is demonstrated for phantoms. CONCLUSION: We demonstrate that a relatively simple change to the CPMG relaxometry sequence parameters from the default setup yields significant improvements in the accuracy and precision of T2 measurements.

Adult↗

PubMed2006

Evaluation of carotid artery wall volume measurement using novel semiautomated analysis software.

PURPOSE: To evaluate semiautomated analysis software for measuring the total carotid arterial wall volume (TWV) as a measure of atheroma burden. MATERIALS AND METHODS: Semiautomated-software and manual analyses of TWV measured by cardiovascular magnetic resonance (CMR) were compared in two phantom models, 10 subjects with no known carotid artery disease, and eight subjects with known carotid disease. The subjects were scanned twice for reproducibility. RESULTS: In subjects with no known carotid disease, semiautomated analysis of 98% of slices showed an improved interstudy coefficient of variation (COV) compared to manual analysis of 50% of slices (4.0% vs. 6.2%, P = 0.02). The proportion of matched cross-sectional slices usable for TWV measurement was superior (99% vs. 49%, P = 0.005) and the median analysis time was shorter (31 minutes vs. 90 minutes, P < 0.001) using the semiautomated software. In subjects with known carotid disease, semiautomated (99% of slices) and manual (56% of slices) analyses had comparable interstudy COVs (4.1% vs. 3.9%, P = 0.01). However, the proportion of matched cross-sectional slices usable for TWV measurement was greater using semiautomated contouring (96% vs. 56%, P = 0.01). CONCLUSION: Carotid CMR measurement of TWV using novel semiautomated analysis software shows good reproducibility, enables greater coverage of arterial vessel wall length, and is considerably faster compared to manual contouring.

Adult↗

PubMed2006

Determination of ion and neutral loss compositions and deconvolution of product ion mass spectra using an orthogonal acceleration time-of-flight mass spectrometer and an ion correlation program.

Exact masses of monoisotopic ions, and the relative isotopic abundances (RIAs) of ions greater in mass by 1 and 2 Da than the monoisotopic ion, are independent and complementary physical properties useful for distinguishing among elemental compositions of ions possible for a given nominal mass. Using these properties to determine elemental compositions of product ions and neutral losses increases the masses of precursor ions for which unique compositions can be determined. Compositions of the precursor ion, product ion, and neutral loss aid mass spectral interpretation and guide modest chemical literature searches for candidate standards to be obtained for confirmation of tentative compound identifications. This approach is essential for compound characterization or identification due to the absence of commercial libraries of electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) product ion spectra. For a series of 34 exact mass measurements, an orthogonal acceleration time-of-flight mass spectrometer provided 34 and 29 values accurate to within 2 and 1 mDa, respectively, for ions from eight simulated unknowns with [M+H](+) ion masses between 166 and 319 Da. Of 36 RIA measurements for +1 Da or +2 Da ions, 35 were accurate to within 20% of their predicted values (or to within 0.4 RIA % when the RIA value was less than 1%) in the absence of obvious interferences, in cases where the monoisotopic ion peak areas were at least 1.7 x 10(5) counts and the ion masses exceeded 141 Da. An ion correlation program (ICP) provided the unique and correct compositions for all but three of the 34 ions studied. Manual inspection of the data eliminated the incorrect compositions. To test the utility of the ICP for deconvoluting composite product ion spectra, all 34 ions were tested for correlation. Six of eight precursor ions were identified as such, while two were compositional subsets of others and were not properly identified. The six precursor ion compositions were still found by the ICP even though ions with masses less than 158 Da were not considered since they could no longer be correlated with a single precursor ion. Finally, two unidentified analytes were characterized, based on data published by others and using the ICP together with mass spectral interpretation.

Acceleration↗

PubMed1993

Risk ratio and rate ratio estimation in case-cohort designs: hypertension and cardiovascular mortality.

Multivariate analysis in case-base designs depends on approximate methods. In the present study, new pseudo-likelihood methods are developed for this design. With these methods, the case-cohort risk ratio and rate ratio as well as their standard errors are easily estimated using logistic regression and Poisson regression, respectively. This is illustrated by the association between hypertension and cardiovascular mortality in a cohort, estimated by case-cohort analysis, using samples of several sizes. The estimates are compared with those obtaining in full-cohort and nested case-control designs. The results indicate that these methods, which require nothing but widely available computer software, are valid. The case-cohort design, therefore, is a good, sometimes even advantageous alternative to the nested case-control design, in studying a disease that is not very rare. Application of the risk ratio method to the full cohort, using a 'sample' of 100 per cent follows logically; whenever the true risk ratio is desired instead of the odds ratio, a multivariate model for its estimation is therefore available.

Adult↗

PubMed1995

Location-scale cumulative odds models for ordinal data: a generalized non-linear model approach.

Proportional odds regression models for multinomial probabilities based on ordered categories have been generalized in two somewhat different directions. Models having scale as well as location parameters for adjustment of boundaries (on an unobservable, underlying continuum) between categories have been employed in the context of ROC analysis. Partial proportional odds models, having different regression adjustments for different multinomial categories, have also been proposed. This paper considers a synthesis and further generalization of these two families. With use of a number of examples, I discuss and illustrate properties of this extended family of models. Emphasis is on the computation of maximum likelihood estimates of parameters, asymptotic standard deviations, and goodness-of-fit statistics with use of non-linear regression programs in standard statistical software such as SAS.

Humans↗

PubMed1998

Using lazy evaluation to simulate realistic-size repertoires in models of the immune system.

We describe a method of implementing efficient computer simulations of immune systems that have a large number of unique B- and/or T-cell clones. The method uses an implementation technique called lazy evaluation to create the illusion that all clones are being simulated, while only actually simulating a much smaller number of clones that can respond to the antigens in the simulation. The method is effective because only 0.001-0.01% of clones can typically be stimulated by an antigen, and because many simulations involve only a small number of distinct antigens. A lazy simulation of a realistic number of clones and 10 distinct antigens is 1000 times faster and 10,000 times smaller than a conventional simulation--making simulations of immune systems with realistic-size repertoires computationally tractable.

Algorithms↗

PubMed1993

Monitoring free-text data using medical language processing.

In this paper, we describe a software system for automated monitoring of free-text data in a medical information system that we call RadTRAC (Radiology Text Report Analyzer and Classifier). RadTRAC uses a medical language processing tool and rules derived from statistical analysis of a database to process free-text chest X-ray (CXR) reports and identify reports that describe new or expanding neoplasms for the purpose of monitoring the follow-up of these patients. To evaluate the RadTRAC system, we examined a set of 470 consecutive radiology reports at the Veterans Administration Medical Center, Palo Alto, CA. We compared RadTRAC classification of CXR reports with retrospective expert classification of the reports and with clinical classification from CXR films as recorded in a logbook while the films were being read. The RadTRAC system had a sensitivity of 90% and a specificity of 82% using the logbook as the gold standard. This was similar to the performance of expert radiologists (sensitivity, 92%; specificity, 90%). We then reviewed the charts, appointment schedule, and subsequent X-ray reports of cases either in the logbook or that were identified by RadTRAC as needing follow-up. Two cases in the logbook could have potentially benefited from an automatic monitoring system to ensure follow-up. RadTRAC identified six confirmed new tumors or new metastatic lesions that were not in the logbook. Six other cases were identified by the RadTRAC system with suspicious X-ray findings that had either no follow-up or no further mention of the X-ray lesion in medical records. This suggests that a reminder system based on the RadTRAC technology would be potentially useful.

Abstracting and Indexing↗

PubMed1997

Visualization-based analysis of multiparameter models using environment for N-dimensional model analysis.

We present a methodology, based on N-dimensional computer visualization, for analyzing multiparameter models. This approach originally consisted of three steps: behavior analysis, sensitivity analysis, identifiability analysis. We have now developed a new way of calculating sensitivity based on the statistical measure of the coefficient of variation. Furthermore, we extended the methodology through the addition of an extra step, visual regression. Visual regression allows the user to visualize the process of actual parameter identification and presents a combined, empirical view of the first three steps in a single image. Next we applied this methodology to pulmonary capillary-transport models. Finally, we implemented the model analysis process as a stand-alone program. EN-DIMAN, the resulting software, allows researchers to carry out model analysis in a graphical user interface (GUI)-based environment.

Algorithms↗

PubMed2000

An algorithm for clustering cDNA fingerprints.

Clustering large data sets is a central challenge in gene expression analysis. The hybridization of synthetic oligonucleotides to arrayed cDNAs yields a fingerprint for each cDNA clone. Cluster analysis of these fingerprints can identify clones corresponding to the same gene. We have developed a novel algorithm for cluster analysis that is based on graph theoretic techniques. Unlike other methods, it does not assume that the clusters are hierarchically structured and does not require prior knowledge on the number of clusters. In tests with simulated libraries the algorithm outperformed the Greedy method and demonstrated high speed and robustness to high error rate. Good solution quality was also obtained in a blind test on real cDNA fingerprints.

Algorithms↗

PubMed1986

An automated technique for analysis of current transitions in multilevel single-channel recordings.

Detailed kinetic studies of ion channel gating are best carried out using the patch-clamp technique which permits the measurement of the ionic current through individual channels. Typical patch-clamp recordings show the current signal, in the form of a sequence of rectangular pulses (analogous to a random telegraph signal), riding on slow baseline drift, partially obscured by high-frequency noise and distorted by filtering. In order to analyze such recordings, we have developed a set of interactive Pascal programs based on a feature-detection algorithm capable of identifying current transitions in multiple-channel recordings in the presence of substantial levels of noise and drift. Software operation is largely automated but includes provisions for examination and correction of the output. The software was optimized and systematically evaluated using simulated data with variable amounts of noise and drift. Results indicate that satisfactory performance is obtained for signal-to-noise ratio as low as four even with uncommonly large baseline drift. Steady-state processing speeds varied from 1,000 to 4,000 samples per second depending on data complexity.

Automation↗

PubMed1990

Experience with gated cardiac software phantoms for quality control of applications programmes.

Ten gated cardiac software phantoms, representing normal and abnormal clinical conditions, were transferred to 9 different computer systems and tested with 11 cardiac programmes. Problems of inappropriate data format were encountered when analysing the phantoms on other systems. The global left ventricular ejection fraction (LVEF) values resulting from the different programmes were compared. Significant programme differences were found, the programmes falling generally into two groups. Few LVEF outlier values were identified. Full functional assessment of cardiac phantoms requires a set of different views which together form the phantom. Application of software phantoms for programme assessment and training requires prudence and attention to the acquired data format, frame time, and gating method for the appropriate use of phantoms.

Computer Simulation↗

PubMed1991

Designing an outcome-oriented computer decision-support system for cardiovascular ICU--a preliminary report.

This paper describes the conceptual framework and preliminary results of an outcome-oriented decision-support system prototype for the cardiovascular intensive care unit (CVICU). The major characteristics of this design include: (1) its problem-based approach to solving clinical problems; (2) an integrated structure with the hospital information system in terms of its data, model and knowledge bases; (3) proposed alternative modes of interaction that include monitoring and critiquing; (4) and research modules that design, manage, and analyze outcome-based clinical studies. At present, an initial prototype has been implemented on a PC as a set of modules accessible from a main menu. The structural framework of the overall system is fairly well defined but only limited quantitative, statistical and expert knowledge has been captured. The second phase of the project involves porting the prototype to a Unix workstation environment, refining and adding models to the model base, expanding its knowledge bases, reasoning capability, and testing the prototype with actual clinical cases in a real-time fashion.

Alberta↗