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MARKOV: a computer program for multi-state Markov models with covariables.

This paper discusses a computer program, called MARKOV, designed to fit a multi-state Markov model with covariables, with a particular emphasis on the analysis of survival data. The Markov model consists of k-1 transient disease states and one absorbing state. The exact transition times are not observed, except in situations such as death. Baseline transition intensities and regression coefficients are estimated via the method of maximum likelihood using a quasi-Newton optimization algorithm. The program's output includes the parameter estimates, the standard error of the estimates, the matrix of the correlation of the estimates and minus two times the log-likelihood function, evaluated at the initial values and at the maximum likelihood estimates. Optionally, survival curves can be generated from each transient state, for one or more combination of covariable values and simple tests about the parameters. The program is illustrated by using a four-state model to determine factors influencing diabetic retinopathy in young subjects with insulin-dependent diabetes mellitus.

Algorithms↗

RefVal: a program implementing the recommendations of the International Federation of Clinical Chemistry on the statistical treatment of reference values.

RefVal is a computer program that implements the recommendations of the International Federation of Clinical Chemistry on the statistical treatment of reference values. The program performs the following main tasks: graphical display of the distribution of reference values, identification or elimination of outliers, testing of the fit of the distribution to Gaussian shape (coefficients of skewness and kurtosis, Anderson-Darling's test, Cramér-von Mises' test, Kolmogorov-Smirnov's test), non-parametric and parametric estimation of reference limits (fractiles, percentiles). The parametric estimation method is based on a two-stage mathematical transformation of data: (1) Manly's exponential transformation (to remove skewness) and (2) John and Draper's modulus transformation (to adjust for remaining kurtosis). The program exists in different versions. The paper describes two of these: (1) a library of FORTRAN functions and subroutines and (2) a Pascal PC program that runs under MS-DOS.

Bias↗

Implementation of linear and quadratic discriminant analysis incorporating costs of misclassification.

Discriminant analysis plays an important role in biological and medical research. In practice, standard linear and quadratic methods are often applied which assume equal costs of misclassification. However, there can be situations where misclassifications between certain groups may be more serious than between other groups. Such considerations can be taken into account by using classification methods which incorporate misclassification costs. The widely applied statistical packages BMDP, SAS, and SPSS do not offer the possibility of using unequal misclassification costs for discriminant analysis with more than two groups. In this paper a menu-driven, user-friendly PC program written in Borland Pascal is introduced which performs linear and quadratic discriminant analysis for g > or = 2 groups allowing for the incorporation of misclassification costs.

Bias↗

Designing clinical trials for two-sided multiple comparisons with a control.

When a clinical trial is to be conducted to compare more than one experimental treatment to a control treatment, Dunnett's two-sided multiple comparison procedure may be proposed to perform the analysis. During the planning stage, the problem of determining the appropriate sample size must be resolved. Here a solution to this problem is derived by controlling the power of the corresponding testing procedure that assumes that the common variance is known.

Arthritis, Rheumatoid↗

An automated patient registration and treatment randomization system for multicenter clinical trials.

This article describes an automated patient registration/treatment randomization system for multicenter clinical trials. Registrations take place centrally using telephone keypads (tone-dial) for data entry and synthesized speech (at the coordinating center) for confirmation. The system permits a wide variety of protocol designs and treatment assignment schemes and presently supports more than 85 protocols of the Pediatric Oncology Group. It is developed in modules to permit easy addition/deletion of studies and treating sites. The system permits uninterrupted, unattended operation at the coordinating center 7 days a week, 24 hours a day.

Clinical Protocols↗

Navigator: tools for informal structure-activity relationship discovery.

Navigator is a molecular database visualization system, designed to support exploratory data analysis and informal structure-activity relationship studies. In addition to the operations commonly found in chemical database systems, it provides new tools that facilitate substituent analysis and help elucidate the relationships among similar molecules and between related assays. Navigator's capabilities include two ways of displaying the relationships between analogs, mouse-sensitive charts of sets of molecules, mouse-sensitive plots of assay relationships, and access to a system for three-dimensional quantitative structure-activity relationship discovery. Navigator's mouse-based user interface provides a one-object/one-window paradigm that makes data manipulation easy even for inexperienced users. Navigator runs on Silicon Graphics workstations.

Computer Graphics↗

FOLD: integrated analysis and display of protein secondary structure.

FOLD, a computer program for the definition and analysis of protein secondary structure, is described. Algorithms implemented in the software are reviewed. These include methods for the identification of simple features such as hydrogen bonds, alpha helices, beta strands, beta bulges, and beta and psi turns. Techniques are also described for the definition and analysis of higher-order structures, such as beta hairpins, beta sheets and their topology, and beta barrels. In addition to considerable textual output the program supports visualization of protein secondary structure in either an atom-based display style or one reproducing the characteristics of a so-called ribbon drawing.

Computer Graphics↗

The fundamentals of object-oriented database management systems.

The purpose of this document is to characterize the two technologies (database and object-oriented technologies) which constitute the foundation of object-oriented database management systems. The O2 Object-Oriented DataBase Management System is then described as an example of this type of system.

Database Management Systems↗

Self-modifying systems: a model for the constructive origin of information.

The mechanisms of information processing in Turning machines and biological systems are examined from the point of view of physical sets of variables. Computation is characterized as a process, the realization of which involves a bounded set of interactions and a pre-definable set of variables in real systems. Using ideas from process philosophy, the ability of natural systems to transcend these computational modes is discussed. A class of systems, called self-modifying systems, that utilize persistent shifts in their defining interactions and variable composition is introduced. Various other ideas that lead to similarly non-computational or semi-computational scenarios (as in the case of distributed code systems) are referenced. As applications, computer models of emergent phenomena using randomly growing interaction sets as well as theoretical issues that range from the meaning of simulation to the problem of information gain in self-modifying systems are discussed.

Computer Simulation↗

Detection, classification and 3D reconstruction of biological macromolecules on hypercube computers.

In this work we present results of the mapping on hypercube computers of some of the key steps involved in the procedure for 3D structural determination from transmission electron microscopy images. The goal is the introduction of parallel processing tools in the field of electron microscopy image processing. We show how the rich topology of the hypercube, combined with an efficient programming strategy, allows for order-of-magnitude increase in computational capacity for such time-consuming tasks as calculation of multidimensional FFT's, cross-correlation coefficients, fuzzy partitioning functionals and the filtered back-projection 3D reconstruction method.

Algorithms↗

Fourier analysis of the forehead shape of skull and sex determination by use of computer.

The forehead shape of the skull was quantified with the Fourier analysis method by using 100 male and 100 female radiographic lateral views of the skull, and sex difference in the forehead shape was studied. Furthermore to predict the sex of cranial specimens, an automated sexing computer system based on the quantification was created. The effectiveness of the system was evaluated by checking 56 male and 56 female specimens of skulls. This system was proved to discriminate male and female skulls from forehead shapes with 85% accuracy.

Adult↗

Simulation of free radical reactions in biology and medicine: a new two-compartment kinetic model of intracellular lipid peroxidation.

To explore mechanisms of free radical reactions leading to intracellular lipid peroxidation in living systems, we developed a computational model of up to 109 simultaneous enzymatic and free radical reactions thought to be involved in the initiation, propagation, and termination of membrane lipid peroxidation. Rate constants for the various reactions were obtained from the published literature. The simulation model included a lipid membrane compartment and an aqueous cytosolic compartment, between which various chemical species were partitioned. Lipid peroxidation was initiated by the iron-catalyzed, superoxide-driven Fenton reaction. A "C" language computer program implemented numerical solution of the steady-state rate equations for concentrations of nine relevant free radicals. The rate equations were integrated by a modified Euler technique to describe the evolution with time of simulated concentrations of hydrogen peroxide, ferric and ferrous iron, unsaturated lipid, lipid hydroperoxides, superoxide anion, and biological antioxidants, including SOD and catalase. Initial results led to significant insights regarding mechanisms of membrane lipid peroxidation: 1. segregation and concentration of lipids within membrane compartments promotes chain propagation; 2. in the absence of antioxidants computed concentrations of lipid hydroperoxides increase linearly about 40 microM/min during oxidative stress; 3. lipid peroxidation is critically dependent upon oxygen concentration and the modeled dependence is similar to the experimental function; 4. lipid peroxidation is rapidly quenched by the presence of Vitamin E-like antioxidants, SOD, and catalase; 5. only small (1 to 50 microM) amounts of "free" iron are required for initiation of lipid peroxidation; 6. substantial lipid peroxidation occurs only when cellular defense mechanisms have been weakened or overcome by prolonged oxidative stress, hence understanding of the balance between free radical generation and antioxidant defense systems is critical to the understanding and control of free radical reactions in biology and medicine.

Antioxidants↗

MR-tutor: a program for teaching the interdependence of factors which influence signal intensity in magnetic resonance imaging.

Magnetic resonance (MR) imaging is a valuable diagnostic radiologic procedure. The appearance of tissues on the MR scan is dependent upon a complex relationship among a number of variables. We have written a computer program which teaches students of magnetic resonance imaging the interdependence of these variables and how they affect the appearance of tissues on MR images. The program is written in BASIC for the IBM* and compatible computers. A listing of the program appears in the Appendix of this article.

Computer-Assisted Instruction↗

Image processing on Macintosh II: a practical boundary finding algorithm for biomedical measurement.

With increasing research interest in displaying and analyzing biomedical images, a practical personal computer based off-line image processing software would be useful. This paper describes the implementation of an image processing work station on a Macintosh II which features a novel edge detection capability useful for biomedical measurement. The boundary finding algorithm is coded in Turbo Pascal, and operates at a speed comfortable for interactive operation. Depending on the complexity of the problem, it usually takes less than a minute for the measurement of an image. The edge detection algorithm has an built-in edge detector with decision-making capability, and can be efficiently controlled by a mouse. In this way, the local accuracy of an automatic edge detection operator, and the global accuracy of the human eye (through manual control of a mouse) are combined.

Algorithms↗

Pseudocolor display of regional organ blood flow determined by means of the radioactive microsphere technique.

The measurement of regional blood flow (RBF) by means of the radioactive microsphere method yields large sets of raw data. In order to display this large volume of data, we have developed a program which provides the user with a graphical illustration of RBF in different organs (e.g., heart, kidney, brain) using various projections and sections. RBF is visualized by a pseudocolor representation. This set-up enables the user to perform a semiquantitative analysis of RBF and provides a tool for the compact representation of the spatial distribution of RBF values in different parts and layers of the organs being studied. The program runs on a standard microcomputer.

Animals↗

A simple computerized tomography adapter for conventional stereotactic frame.

This paper introduces a new technique to convert a conventional Leksell stereotactic frame into a computerized tomography compatible system. Accurate calculation of the tumour coordinates can be made by means of two adapter plates with double diagonal lines on each side thus obviating the requirement of careful alignment of the scanner. The adapter plates are of simple design and easy to prepare.

Brain Diseases↗

FAMIS: a software package for functional feature extraction from biomedical multidimensional images.

An increased number of image sequences is acquired in all modalities of the biomedical imaging field in order to study displacement or metabolism of a tracer or a contrast agent. It requires effective processing methods to estimate the underlying physiological components. We have developed a software package based on factor analysis algorithms which can adapt to various imaging modalities and its extension to double-indexed image sequences. We describe general characteristics of the software and present the main points of the user-friendly interface. The performances of the package are discussed and the possibilities of the methodology are illustrated using an example in magnetic resonance imaging.

Algorithms↗

Validation of a reference method for correlation of anatomic and functional brain images.

We describe a reference device that provides accurate correlations between anatomic and functional brain images. The reference device, which generates fiduciary reference points on sequential scan planes, is positioned adjacent to the orbitomeatal line of the subject, and held in place by a framework anchored to the external auditory meatus. The reference system was tested on 17 subjects undergoing Tc-99m-hexamethylpropyleneamine oxime (Tc-99m-HM-PAO) brain single photon emission computed tomography (SPECT) and cranial computed tomography (CT) scans. The centers of the caudate nuclei, thalami, brain stem, and cerebellar vermis were identified independently on CT and SPECT. The average difference +/- 1 sd between structure locations (x, y, and z) on SPECT and CT were calculated as 1.86 +/- 1.5, 2.16 +/- 1.4, and 1.83 +/- 1.9 mm, respectively. The relevance of the method to clinical applications is illustrated by the localization of a recurrent viable glioma and an epileptogenic focus. This reference system provides an accurate, rapid, and noninvasive patient-specific method for the correlation of brain structure with brain function.

Brain↗