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In this article, we show how to apply our previously proposed Deletion/Substitution/Addition algorithm in the context of right-censoring for the prediction of survival. Furthermore, we introduce how to incorporate bagging into the algorithm to obtain a cross-validated bagged estimator. The method is used for predicting the survival time of patients with diffuse large B-cell lymphoma based on gene expression variables.
PURPOSE: To describe a new method of measuring posterior capsule opacification (PCO) and intraocular lens (IOL) rotation and report the validation of the method. SETTING: Ophthalmology Department, St. Thomas' Hospital, and Medical Imaging, Department of Physics, King's College, London, United Kingdom. METHOD: A new interactive software program, POCOman, was developed for the semiobjective assessment of PCO. Digital images of the posterior capsule, which can be acquired by any technique, are analyzed by the observer to determine the percentage area of PCO and assign a severity score. The system was validated by comparing it to clinical slitlamp evaluation of PCO and automated POCO system analysis using a library of 100 images taken from archives. The software also measures sequential IOL rotation for the evaluation of toric IOLs. RESULTS: An image could be analyzed in approximately 2 minutes. The results of the POCOman system correlated well with the results of the automated POCO system and clinical evaluation. CONCLUSIONS: The POCOman is an effective, user-friendly system for quantifying PCO. It can be obtained for free and has advantages over other methods.
BACKGROUND: Automatic and semi-automatic algorithms to calculate ejection fraction (EF) from planar radionuclide ventriculography (PRV) have been used for many years in nuclear medicine. Validation of these algorithms is scarce and often performed on outdated versions of the software. Nevertheless, clinical trials where PRV is being used as the 'gold standard' for EF are numerous. Because of the importance attributed to the EF calculated by these programs, the accuracy of the resulting EF was assessed with a dynamic left ventricular physical phantom. METHODS: A dynamic left ventricular phantom was used to simulate 21 combinations of various ejection fractions (7-66%) and end diastolic volumes (27-290 ml). For each combination, a planar radionuclide ventriculograph was acquired, converted to an interfile format and transferred into processing stations with 10 different contemporaneously available commercial algorithms. The gold standard was the 'real' EF of the phantom, derived from the exact volume of the ventricle in end diastolic and end systolic position. Correlation and Bland-Altman analysis was performed between the real EF and the calculated EF. RESULTS: The correlation for all data was excellent (r=0.98), the mean difference was very acceptable (0.98%). Nevertheless, Bland-Altman analysis showed a significant trend in the difference between real and calculated EF, with a growing underestimation for higher ranges of EF, due to an overestimation of background in larger volumes compared to smaller ones. CONCLUSION: The determination of EF from PRV, calculated with commercially available algorithms, correlates closely to the real EF of a dynamic left ventricular phantom. This phantom can be used in the development and validation of algorithms for PRV studies, in software audits and in quality assurance procedures.
A simple, accurate, and effective capillary electrophoresis method with ultraviolet absorbance detection was developed and validated for the quantitation of the antihistamine fexofenadine in capsules. The separation was performed with an uncoated fused-silica capillary (47 cm x 75 microm id) and was operated at 20 kV potential. Temperature was maintained at 25 degrees C. The run buffer was prepared with 20mM Na2B4O7 x 10 H2O. Software was used for system control, data acquisition, and analysis. Method validation was performed by evaluation of the analytical parameters linearity, precision, accuracy, limits of detection and quantitation, and specificity. The method was linear (r = 0.9999) at concentrations ranging from 20 to 100 microg/mL, precise (relative standard deviation intra-assay = 1.2, 1.6, and 1.8% and interassay = 1.5%); accurate (recovery = 98.1%); and specific. The limits of detection and quantitation were 0.69 and 2.09 microg/mL, respectively. The method was compared to the liquid chromatography method developed previously by the authors for the same drug, and no significant difference was found between the 2 methods in fexofenadine hydrochloride quantitation.
Design of locus-specific primers for use during genetic analysis requires combining information from multiple sources and can be a time-consuming process when validating large numbers of assays. Data warehousing of genomic DNA sequences and genetic variations when coupled with software applications for optimizing the generation of locus-specific primers can increase the efficiency of assay development. Selection of oligonucleotide primers for PCR and Pyrosequencing (SOP3) software allows user-directed queries of warehoused data collected from the human and mouse genome sequencing projects. The software automates collection of DNA sequence flanking single-nucleotide polymorphisms (SNPs) as well as the incorporation of locus-associated functional information, such as whether the SNP occurs in an exon, intron, or untranslated region. SOP3 software accepts three types of user-directed input consisting of gene locus symbols, SNP reference sequence numbers, or chromosomal physical location. For human polymorphisms, SOP3 incorporates haplotype, ethnicity, and SNP validation attributes. The output is a list of oligonucleotide primers recommended for Pyrosequencing-based typing of genetic variations. SOP3 is available at the Division of Immunogenetics computational server found at http://imgen.ccbb.pitt.edu.
The Applied Biosystems (ABI) Prism 377 DNA sequencer has been evaluated in an attempt to increase the throughput of samples for short tandem repeat (STR) analysis, in both forensic casework and the UK National Criminal Intelligence DNA Database. The gel system assessed consisted of 0.2 mm, 4% acrylamide 6 M urea gels, with a well-to-read distance of 36 cm. Gels were run at a constant voltage of 3 kV and constant temperature of 51 degrees C. The run time of our second generation multiplex (SGM) STR system was achieved in less than 2 h. Rigorous validation has been performed on the instrument hardware and software. Complete resolution of 1 base differences was obtained, up to and beyond 350 bases; sizing precision across gels was more than 2-fold higher than the 373A and the sensitivity was increased by one third.
Quantitative tissue Doppler echocardiography is a new diagnostic approach to left ventricular systolic performance. The aim of the present study was to validate a recently developed method based on the computer software TDI-Labor enabling a variable time and space related measurement of regional wall velocity from tissue Doppler images. Therefore, in 63 volunteers the mean velocity of a 2 mm thick subendocardial slice during the systolic ejection period was determined from frozen tissue Doppler M-mode images of the left ventricular posterior wall obtained using the left parasternal window. The same images were employed for comparative measurement of the mean endocardial velocity using the conventional M-mode slope approach. Tissue Doppler data of the subendocardial wall velocity were found to correspond closely to the mean endocardial wall velocity (y = 0.97x + 0.17; r = 0.77; p < 0.0001). The average wall motion gradient of the population was 1.33 +/- 0.35. Wall motion velocity and wall motion gradient were shown to be not age dependent. The new software approach to an improved analysis of wall motion offering any sized sample volumes and time intervals for wall velocity measurements can be regarded as an exact and easily feasible method. Further clinical and experimental investigations are needed to evaluate its diagnostic relevance to the detection of ischemia and other myocardial dysfunction.
The relative content of myosin heavy chain (MHC) isoforms IIb, IIa and I in human skeletal muscle taken from the m. vastus lateralis of 30 healthy male subjects was analysed using mini-gel electrophoresis. Repeated electrophoretic gels utilizing the same methods were produced for all subjects and the determination of MHC protein bands was performed using a digital scanner and National Institutes of Health (NIH) Image software and laser densitometry. A comparison between the NIH Image processing technique and laser densitometry revealed differences of 6.47%, 6.35% and 6.84% between these measurement techniques for MHC-IIb, -IIa and -I isoforms, respectively. The percentage technical error of measurement (TEM%) between electrophoretic gels was shown to be 19.1%, 17.8% and 14.2%, with regard to percentage of occurrence of MHC-IIb, -IIa and -I isoforms respectively. The variation in electrophoretic gel analyses was shown to be 5.7%, 7.3% and 5.5%, with regard to the percentage of MHC-IIb, -IIa and -I isoforms respectively. Intra-class correlations comparing NIH Image and laser densitometry produced r values in the range 0.38-0.63. Comparisons between and within gel analyses produced r values in the range 0.59-0.94 and 0.93-0.98, respectively. Analyses of variance revealed no significant differences (P < 0.05) between analysis techniques, between gels or within gels for the measurement of MHC-IIb, -IIa and -I isoforms. The inter-gel error between fibre subgroups was moderate for the two type-II MHC populations and less for type-I MHC; the intra-individual error in the measuring technique used for classifying the MHC-IIb, -IIa and -I protein bands was small. The results obtained in this investigation showed consistent trends which may reflect a false classification of the type-II MHC populations for the inter-gel and intra-individual analyses. The NIH Image software and digitizing process was shown to be a valid and reliable method for distinguishing between MHC protein bands of human skeletal tissue as separated by mini-gel electrophoretic techniques.
Dynamic changes in cardiac structure and function are usually examined by real-time imaging techniques such as angiography or echocardiography. MRI has many advantages compared with these established cardiac imaging modalities. However, system hardware and software limitations have limited cardiac MRI to gated acquisitions that are lengthy and often result in failed acquisitions and examinations. Recently, MRI has evolved into a technique capable of imaging dynamic processes in real time. Improvements in hardware, pulse sequences, and image reconstruction algorithms have enabled real-time cardiac MRI with high spatial resolution, high temporal resolution, and various types of image contrast without requiring cardiac gating or breath-holding. This article provides an overview of current capability and highlights key technical and clinical advances. The future prospects of real-time cardiac MRI will depend on 1) the development of techniques that further improve signal to noise ratio, contrast, spatial resolution, and temporal resolution, without introducing artifacts; 2) the development of software infrastructure that facilitates rapid interactive examination; and 3) the development and validation of several new clinical assessments.
A microcomputer-based video system for tracking, recording, and analyzing the movement of animals in two dimensions on variegated background in real-time has been developed and validated, both mechanically and with moving animals. Hardware and software (donationware) costs are low. Specimens visualized as small as 3 pixels long may be tracked in an arena that is 240 x 320 pixels in size. The results of tracking a mechanical moving spot are compared with a theoretical circular path. Comparisons between frame-by-frame human observation and computer generated X-Y coordinates are also presented. Applications of the tracking system include insect toxicology and pheromone bioassay, vertebrate locomotion studies, and basic research on taxes and kineses.
Neurons perform much of their integrative work in the dendritic tree, and spinal motoneurons have the largest tree of any cell. Electrical excitability is strongly influenced by dendrite membrane properties, which are difficult to measure directly. We describe a method to measure the distribution of ion channel membrane densities along dendritic trajectories. The method combines standard immunohistochemistry with reconstruction procedures for both large-scale and small-scale optical microscopy. Software written for Matlab then extracts the colocalization of the target ion channel with the target dye injected cell, and calculates the relative channel density per square micron of cell surface area, as a function of distance from the cell body. The technique can be used to quantify the localization and distribution of any immunoreactive moiety, and the software provides a flexible vehicle for sensitivity analysis, to validate heuristics for selecting thresholds.
A new magnetic arrangement is described for use with an in-plane electromagnetic acoustic transducer (EMAT) for detecting laser-generated ultrasound. The magnetic flux density was modelled and validated. Modelling was accomplished in 3D using finite element software to predict new magnet spatial distributions. A configuration was found which increased the magnetic flux density by a factor of 1.8+/-0.2, compared to magnetic configurations previously used in conventional designs. Model predictions were implemented and confirmed experimentally. As a result, laser ultrasound Rayleigh waves have been used to verify the performance of this sensor system. It was establish that the EMAT's in-plane sensitivity increased, while the frequency bandwidth improvement factor was about 1.9+/-0.2. The resonant frequency increased from 6.5 MHz and 16.4 MHz, with both exhibiting an extended frequency response well beyond the resonant values. For maximum frequency response, it was demonstrated that added elements such as cables may have a deleterious effect. In particular the length of the cable, which in turn adds capacitance to the overall circuit, will decrease the frequency response of the EMAT. The frequency response was compared with a previous sensor, to provide an increased resonant frequency factor of 2.5+/-0.2.
One of the primary goals of computer-aided ergonomics is to develop software tools that allow ergonomics information to be accessed at the earliest stages of design. This case study discusses a PC-based software program that allows a designer to quantify a worker's biomechanical risk for injury based on a proposed workplace design. The program couples an established software tool for biomechanical analysis, the Three-Dimensional Static Strength Prediction Program (3DSSPP), with a widely used computer-aided design software package, AutoCAD. The use of this "3DSSPP/AutoCAD interface" in the proactive analysis of an automotive assembly task is described and the results compared with an independent assessment using observations of workers performing the same task. Both studies yield similar conclusions, suggesting that proactive use of software such as the 3DSSPP/AutoCAD interface may be a valid tool in evaluating proposed workplace designs. In this context, issues in the analysis of workplace designs regarding the use of supporting ergonomic tools, assumptions, and posture selection are discussed.
This study describes major electrocardiogram (ECG) measurements and diagnoses in a population of African individuals; most reference data have been collected in Caucasian populations and evidence exists for interethnic differences in ECG findings. This study was conducted in the Seychelles islands (Indian Ocean) and included 709 black individuals (343 men and 366 women) aged 25 to 64 years randomly selected from the general population. Resting ECG were recorded by using a validated ECG unit equipped with a measurement and interpretation software (Cardiovit AT-6, Schiller, Switzerland). The epidemiology of 14 basic ECG measurements, 6 composite criteria for left ventricular hypertrophy and 19 specific ECG diagnoses including abnormal rhythms, conduction abnormalities, repolarization abnormalities, and myocardial infarction were examined. Substantial gender and age differences were found for several ECG parameters. Moreover, tracings recorded in African individuals of the Seychelles differed from those collected similarly in Caucasian populations in many respects. For instance, heart rate was approximately 5 beats per minute lower in the African individuals than in selected Caucasian populations, prevalence of first degree atrio-ventricular block was especially high (4.8%), and the average Sokolow-Lyon voltage was markedly higher in African individuals of the Seychelles compared with black and white Americans. The integrated interpretation software detected "old myocardial infarction" in 3.8% of men and 0% of women and "old myocardial infarction possible" in 6.1% and 3%, respectively. Cardiac infarction injury scores are also provided. In conclusion, the study provides reference values for ECG findings in a specific population of people of African descent and stresses the need to systematically consider gender, age, and ethnicity when interpreting ECG tracings in individuals.
Disinfection by-products (DBPs) are produced as a result of disinfecting water using various treatment methods. Over the years, chlorine has remained the most popular disinfecting agent due to its ability to kill pathogens. However, in 1974, it was discovered that the superchlorination of drinking water resulted in the production of chloroform and other trihalomethanes. Since then hundreds of additional DBPs have been identified, including haloacetic acids and haloacetonitriles with very little or no toxicological data available, thus necessitating the use of additional methods for hazard estimation. Quantitative Structure Toxicity Relationship (QSTR) is one such method and utilizes a computer-based technology to predict the toxicity of a chemical solely from its molecular attributes. The current research was conducted utilizing the TOPKAT/QSTR software package which is comprised of robust, cross-validated QSTR models for assessing mutagenicity, rodent carcinogenicity (female/male; rat/mouse), developmental toxicity, skin sensitization, lowest-observed-adverse-effect level (LOAEL), fathead minnow LC(50), rat oral LD(50) and Daphia magna EC(50). A total of 252 DBPs were analyzed for the likelihood that they would produce tumors and developmental effects using the carcinogenicity and developmental toxicity submodels of TOPKAT. The model predictions were evaluated to identify generalizations between the functional groups (e.g. alcohols, acids, etc.) and specific toxic endpoints. Developmental toxicity was identified as an endpoint common to the majority of aliphatic mono- and dicarboxylic acids, aliphatic halogenated and non-halogenated ketones, and aliphatic haloacetonitriles. In the case of the carcinogenicity submodels, most aliphatic aldehydes were identified as carcinogens only in the female mouse submodel. The majority of the aliphatic and aromatic dicarboxylic acids were identified as carcinogens in the female rat submodel. All other functional groups examined were largely predicted as non-carcinogens in all the cancer submodels (i.e. male/female rats and mice). The QSTR results should aid in the prioritization for evaluation of toxic endpoints in the absence of in vivo bioassays.
We report the first large-scale gel-free proteomic analysis of the soluble subproteome of the emerging pathogen Ochrobactrum anthropi. Utilizing our robust offline multidimensional protein identification protocol, a total of 57 280 peptides were initially identified utilizing automated MS/MS analysis software. We describe our investigation of the heuristic protein validation tool PROVALT and demonstrate its ability to increase the speed and accuracy of the curation process of large-scale proteomic datasets. PROVALT reduced our peptide list to 8517 identified peptides and further manual curation of these peptides led to a final list of 984 uniquely identified peptides that resulted in the positive identification of 249 proteins. These identified proteins were functionally classified and physiochemically characterized. A variety of typical "housekeeping" functions identified within the proteome included nucleic acid, amino and fatty acid anabolism and catabolism, glycolysis, TCA cycle, and pyruvate and selenoamino acid metabolism. In addition, a number of potential virulence factors of relevance to both plant and human disease were identified.
The value of comparative molecular modeling for elucidating structure-function relationships was demonstrated by analyzing six anti-nucleosome autoantibody variable fragments. Structural models were built using the automated procedure developed in the COMPOSER software, subsequently minimized with the AMBER force field, and validated according to several standard geometric and chemical criteria. Canonical class assignment from Chothia and Lesk's [Chottin and Lesk, J. Mol. Biol., 196 (1987) 901; Chothia et al., Nature, 342 (1989) 877] work was used as a supplementary validation tool for five of the six hypervariable loops. The analysis, based on the hypothesis that antigen binding could occur through electrostatic interactions, reveals a diversity of possible binding mechanisms of anti-nucleosome or anti-histone antibodies to their cognate antigen. These results lead us to postulate that antinucleosome autoantibodies could have different origins. Since both anti-DNA and anti-nucleosome autoantibodies are produced during the course of systemic lupus erythematosus, a non-organ specific autoimmune disease, a comparative structural and electrostatic analysis of the two populations of autoantibodies may constitute a way to elucidate their origin and the role of the antigen in tolerance breakdown. The present study illustrates some interests, advantages and limits of a methodology based on the use of comparative modeling and analysis of molecular surface properties.
MOTIVATION: We address the problem of identifying gene transcriptional modules from gene expression data by proposing a new approach. Genes mostly interact with each other to form transcriptional modules for context-specific cellular activities or functions. Unraveling such transcriptional modules is important for understanding biological network, deciphering regulatory mechanisms and identifying biomarkers. METHOD: The proposed algorithm is based on two-stage matrix decomposition. We first model microarray data as non-linear mixtures and adopt the non-linear independent component analysis to reduce the non-linear distortion and separate the data into independent latent components. We then apply the probabilistic sparse matrix decomposition approach to model the 'hidden' expression profiles of genes across the independent latent components as linear weighted combinations of a small number of transcriptional regulator profiles. Finally, we propose a general scheme for identifying gene modules from the outcomes of the matrix decomposition. RESULTS: The proposed algorithm partitions genes into non-mutually exclusive transcriptional modules, independent from expression profile similarity measurement. The modules contain genes with not only similar but different expression patterns, and show the highest enrichment of biological functions in comparison with those by other methods. The usefulness of the algorithm was validated by a yeast microarray data analysis. AVAILABILITY: The software is available upon request to the authors.