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Markov chain Monte Carlo methods in biostatistics.

Appropriate models in biostatistics are often quite complicated. Such models are typically most easily fit using Bayesian methods, which can often be implemented using simulation techniques. Markov chain Monte Carlo (MCMC) methods are an important set of tools for such simulations. We give an overview and references of this rapidly emerging technology along with a relatively simple example. MCMC techniques can be viewed as extensions of iterative maximization techniques, but with random jumps rather than maximizations at each step. Special care is needed when implementing iterative maximization procedures rather than closed-form methods, and even more care is needed with iterative simulation procedures: it is substantially more difficult to monitor convergence to a distribution than to a point. The most reliable implementations of MCMC build upon results from simpler models fit using combinations of maximization algorithms and noniterative simulations, so that the user has a rough idea of the location and scale of the posterior distribution of the quantities of interest under the more complicated model. These concerns with implementation, however, should not deter the biostatistician from using MCMC methods, but rather help to ensure wise use of these powerful techniques.

Algorithms↗

Decreases in ventricular volume correlate with decreases in ventricular pressure in idiopathic normal pressure hydrocephalus patients who experienced clinical improvement after implantation with adjustable valve shunts.

OBJECTIVE: This retrospective study examined whether changes in ventricular volume correspond with changes in adjustable valve pressure settings in a cohort of patients who received shunts to treat idiopathic normal pressure hydrocephalus. We also examined whether these pressure-volume curves and other patient variables would co-occur with a positive clinical response to shunting. METHODS: We selected 51 patients diagnosed with idiopathic normal pressure hydrocephalus who had undergone implantation of a Codman Hakim programmable valve (Medos S.A., Le Locle, Switzerland). Clinical data were gathered from the patients' records and clinical notes by an investigator blinded to patients' ventricular volumes. Ventricular volume was measured using 3D Slicer, an image analysis and interactive visualization software package developed and maintained at the Surgical Planning Laboratory at Brigham and Women's Hospital. RESULTS: Eighty-six percent of patients with gait disturbance at presentation showed improvement of this symptom, 70% experienced improvement in incontinence, and 69% experienced improvement in dementia. For the group showing 100% clinical improvement, the correlation coefficient of average changes in valve pressure over time (delta P/delta T) and average changes in ventricular volume over time (delta V/delta T) were high at 0.843 (P < 0.05). For the group experiencing no or only partial improvement, the correlation coefficient was 0.257 (P = 0.32), indicating no correlation between average delta V/delta T and average delta P/delta T for each patient. CONCLUSION: This was a carefully analyzed modeling study of idiopathic normal pressure hydrocephalus treatment made possible only by adjustable valve technology. With careful volumetric analysis, we found that changes in ventricular volume correlated with adjustments in valve pressure settings for those patients who improved clinically after shunting. This suggests that positive clinical responders retained parenchymal elasticity, emphasizing the importance of dynamic changes in this cohort.

Adolescent↗

Improving synthetic efficiency using the computational prediction of biological activity.

A process has been developed whereby libraries of compounds for lead optimization can be synthesized and screened with greater efficiency using computational tools. In this method, analogues of a lead chemical structure are considered in the form of a virtual library. Less than 1/3 of the library is selected as a training set by clustering the compounds and choosing the centroid of each cluster. This training set is then used to generate a model using PLS regression upon the experimental values from that assay using 1D/2D descriptors. The model is applied to the remaining compounds (the test set) for which assay values are predicted and a rank ordering established. An example of this was a set of 169 PDE4 inhibitors. A predictive model was achieved using a training set of 52 compounds. When applied to the remaining 117 compounds this model allowed a rank ordering of these compounds for synthesis and testing. Selecting the top 33 compounds of the test set gives 78% of the compounds with the desired activity (hits) by synthesizing only 50% of the library, including the training set. Selecting the top 59 of the test set gives 97% of the hits from only 67% of the library. This process succeeds by avoiding two principal weaknesses of 2D descriptors: lack of interpretation and lack of extrapolation. Two principal assumptions of QSAR are shown to be unnecessary; removing descriptor redundancy does not improve fit and a predictive r2 greater than 0.5 is not necessary if rank-ordering is desired.

3',5'-Cyclic-AMP Phosphodiesterases↗

A package for cost and critical analysis of picture archiving and communication indicating its true yield (CAPACITY).

The hospital-wide use of picture archiving and communication systems (PACS) promises a number of advantages in the future. These benefits will only be obtained at considerable costs, however. In view of the rapidly developing technology the costs of hardware can be expected to decrease. The ideas about the expected moment when the benefits will exceed the costs show wide variation. In order to get a better view on the cost comparison between PACS and the classical film-based system and also to stimulate discussions on this topic, a software package called CAPACITY (cost and critical analysis of picture archiving and communication indicating its true yield) has been developed by BAZIS within the scope of its IMAGIS (image information system) project. CAPACITY calculates the costs in the year of introduction for both situations, conventional and PACS, based on the consumption or use of the various resources (e.g. film, optical disks, manpower in the archive, operators, network, workstations etc.) needed for the production of the radiological department. These two costs are calculated for a series of years, thus giving an indication for the moment of breakeven. User-supplied data is interrelated and checked for plausibility against a number of expert given rules of thumb by CAPACITY's critique module. The first results and experiences acquired during a pilot study using a prototype version of the package will be discussed. The CAPACITY package is available for evaluation and trial (only distribution costs will be charged if experiences and results are returned).

Computer Simulation↗

Data integration to assist gastric emptying data analysis.

The diagnosis of dyspepsia is very difficult because the symptoms are clinically aspecific and the gastric emptying time tests are of complex interpretation. An integrated and automated analysis of clinical and instrumental data may improve the diagnostic process. We present a system to collect data on dyspeptic patient from different sources which has been set up to assist the clinician in the diagnosis of dyspepsia. The data base integrates a wide set of symptoms with data coming from laboratory tests. Moreover, we assess the feasibility of classifying gastric emptying profiles using both octanoid acid excretion data and electrogastrography.

Adult↗

MR imaging volumetry of subcortical structures and cerebellar hemispheres in normal persons.

BACKGROUND AND PURPOSE: Volume changes in subcortical structures and cerebella have been associated with localization-related epilepsy and psychiatric illnesses. This study evaluated the effect of handedness and sex on the volumes of selected subcortical structures and cerebellar hemispheres in normal persons. METHODS: Volumetric measurements were performed of the caudate heads, thalami, and cerebellar hemispheres in 34 (20 right- and 14 left-handed, 19 female and 15 male) normal persons. Amygdalar and hippocampal volumes were reported previously for these persons. All study participants completed a 10-item handedness questionnaire. The MR imaging sequence was a 3D T1-weighted gradient-echo acquisition of the whole brain (24/6 [TR/TE]; flip angle, 25 degrees). MR images were spatially normalized, and volumes were painted with a 1.0 mm(3) resolution cursor on an SGI workstation. The effects of handedness and sex on standardized volumes and right-to-left volume ratios were calculated, and volumes were compared between right and left sides for each structure. RESULTS: Handedness did not affect standardized volumes or asymmetries of the caudate heads, thalami, or cerebellar hemispheres. The volumes of subcortical structures were bilaterally larger in women than in men. Right-to-left asymmetries were significant for the caudate head and cerebellum but not for the thalamus. CONCLUSION: These findings show that women have significantly larger subcortical structures than do men after spatial normalization to account for differences in brain size. Sex-specific normal ranges may be needed for evaluating volume changes related to epilepsy or other disease processes.

Adult↗

Reproducibility of functional MR imaging results using two different MR systems.

BACKGROUND AND PURPOSE: In the application of functional MR imaging for presurgical planning, high reproducibility is required. We investigated whether the reproducibility of functional MR imaging results in healthy volunteers depended on the MR system used. METHODS: Visual functional MR imaging reproducibility experiments were performed with 12 subjects, by using two comparable 1.5-T MR systems from different manufacturers. Each session consisted of two runs, and each subject underwent three sessions, two on one system and one on the other. Reproducibility measures D (distance in millimeters) and R(size) and R(overlap) (ratios) were calculated under three conditions: same session, which compared runs from one session; intersession, which compared runs from different sessions but from the same system; and intermachine, which compared runs from the two different systems. The data were averaged per condition and per system, and were compared. RESULTS: The average same-session values of the reproducibility measures did not differ significantly between the two systems. The average intersession values did not differ significantly as to the volume of activation (R(size)), but did differ significantly as to the location of this volume (D and R(overlap)). The average intermachine reproducibility did not differ significantly from the average intersession reproducibility of the MR system with the worst reproducibility. CONCLUSION: The location of activated voxels from visual functional MR imaging experiments varied more between sessions on one MR system than on other MR system. The amount of the activated voxels is independent of the MR system used. We suggest that sites performing functional MR imaging for presurgical planning measure the intersession reproducibility to determine an accurate surgical safety margin.

Adult↗

[Experimental evaluation of dynamic MRI for quantifying liver perfusion].

Gadolinium-DTPA enhanced dynamic MR imaging is a new method for the quantification of portal bloodflow and liver perfusion. In this study we evaluated the validity of this method comparing it with thermodiffusion and dopplerflowmetry in pigs. We found a significant correlation of tissue perfusion between dMRI and thermodiffusion and of portal bloodflow between dMRI and dopplerflowmetry. Partial occlusion of the portal vene was accurately detected by dMRI. Dynamic MRI could become a valuable diagnostic method for the quantification of liver perfusion.

Animals↗

Quantitative assessment of parenchymal and ventricular readjustment to intracranial pressure relief.

A 26-year-old patient underwent endoscopic third ventriculostomy for the treatment of obstructive hydrocephalus. 3D volume data sets were obtained at 3 T before surgery and three times after surgery. Off-line analysis of individual imaging data (initial linear registration, intensity adjustment, and final nonlinear registration of pre- to postoperative MR images) yielded 3D displacement fields representing the postoperative structural brain change. In principle, such an analysis technique can be used in any clinical follow-up for which careful observation of tissue readjustment is of particular importance.

Adult↗

Maximum likelihood training of connectionist models: comparison with least squares back-propagation and logistic regression.

This paper presents maximum likelihood back-propagation (ML-BP), an approach to training neural networks. The widely reported original approach uses least squares back-propagation (LS-BP), minimizing the sum of squared errors (SSE). Unfortunately, least squares estimation does not give a maximum likelihood (ML) estimate of the weights in the network. Logistic regression, on the other hand, gives ML estimates for single layer linear models only. This report describes how to obtain ML estimates of the weights in a multi-layer model, and compares LS-BP to ML-BP using several examples. It shows that in many neural networks, least squares estimation gives inferior results and should be abandoned in favor of maximum likelihood estimation. Questions remain about the potential uses of multi-level connectionist models in such areas as diagnostic systems and risk-stratification in outcomes research.

Diagnosis, Computer-Assisted↗

[Stress distribution in the brain--numerical simulation by the finite element method].

The analysis of the deformation of brain and distribution of stress caused by the compression from outside would be interesting and also useful for the better understanding of the pathophysiology in the cases of intracranial hematoma and other space occupying lesions. The computerized numerical simulation using the finite element method was carried out to analyze these problems. A simple brain model of two dimensions, that was composed of the inner surface of skull, brain and lateral ventricles, was utilized and it was divided into 101 triangular elements for the calculation of finite element method by a 16-bit personal computer. The model of brain was compressed in two different ways; one was a subdural hematoma type where the force of compression was distributed over relatively wide area and the other was a epidural hematoma type where compression was localized to smaller area. In both types, the brain was compressed on the left fronto-temporal region. The deformation of brain in the subdural hematoma type model was that corresponding to the hematoma of crescent shape just as seen on the CT scan of actual case. The lateral ventricle of affected side was deformed more markedly than that of contralateral side. The midline structure of the brain was shifted to normal side and shift was larger in the portion anterior to the lateral ventricles. The stress was distributed from the area beneath the hematoma to remote location in the affected hemisphere but the propagation of stress was blocked by the falx and it was very small in the contralateral hemisphere.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain↗

A service-oriented information sources database for the biological sciences.

Researchers in the biological sciences require access to a variety of information sources located in various places on different computer networks. In order to satisfy the information needs of a researcher, appropriate information sources must be selected and access to these information sources and the computing services supporting them must be provided in a way that does not distract the researcher from problems of real interest. At the University of Missouri-Columbia a service-oriented information sources database is being developed as a key component of a layered-model design of an intelligent system which will provide a research environment appropriate to the needs of researchers in the biological sciences.

Artificial Intelligence↗

An information system for epidemiology based on a computer-based medical record.

A new way is presented to build an information system addressed to problems in epidemiology. Based on our analysis of current and future requirements, a system is proposed which allows for collection, organization and distribution of data within a computer network. In this application, two broad communities of users-physicians and epidemiologists-can be identified, each with their own perspectives and goals. The different requirements of each community lead us to a client-service centered architecture which provides the functionality requirements of the two groups. The resulting physician workstation provides help for recording and querying medical information about patients and from a pharmacological database. All information is classified and coded in order to be retrieved for pharmaco-economic studies. The service center receives information from physician workstations and permits organizations that are in charge of statistical studies to work with "real" data recorded during patient encounters. This leads to a new approach in epidemiology. Studies can be carried out with a more efficient data acquisition. For modelling the information system, we use an object-oriented approach. We have observed that the object-oriented representation, particularly its concepts of generalization, aggregation and encapsulation, are very usable for our problem.

Computer Communication Networks↗

[The revised PEDINFUS computer program for total and added parenteral nutrition in children].

The computer program PEDINFUS, first described in 1991, has been fundamentally revised and further developed. The area of application has been considerably widened as additive parenteral nutrition has been included and the group of newborn and preterm infants has been taken into account. Consequently, the program can be used for children of all age groups. In addition, the program has a graphical user interface and can be used on several hardware platforms. The flexibility of the program has also been increased to a considerable degree. Now the nutrient amounts per kilogram per day, the limits of the laboratory values, the combination of enteral food and infusion solutions, and the already drawn-up infusion plans can be changed at liberty. Considerably more matters of clinical interest accompanying parenteral nutrition have been integrated in the program. Further plausibility controls have also been introduced to achieve greater certainty in the calculation of the infusion solutions. In consequence, the preconditions for ensuring and controlling the quality of infusion therapy regimens can be established on an improved level.

Adolescent↗

[Database for assessment of treatment results in patients with multiple trauma].

Data base for assessment of results of treatment of politrauma patients is presented. It was created on the basis of Abbreviated Injury Scale, Injury Severity Score and Revised Trauma Score. Examination was supplemented with TRISS method inclusive of graphic assessment PRE-CHART and statistic Z and M. The software was created on the basis of Excel 7.0 and Windows 95.

Computer Graphics↗

Choice of antibiotics by the site of infection in a community hospital.

A total of 1578 culture and antimicrobial susceptibility results on clinical specimens from various sites of infection were analyzed, by using the software installed in the MicroScan System of an automated microbiology analyzer, and by mathematical calculation. A list of antimicrobial drugs of choice by the site of infection is determined on the basis of the computer and mathematical analysis of the above data. The list suggested in this in vitro study may be useful to clinicians for selection of an initial antimicrobial agent in hospitals or communities when an infection is suspected in a site of infection before the results of cultures and antimicrobial susceptibility tests are reported. This list may also be helpful for initial therapy in critically ill patients before ordering culture and susceptibility testing, as well as for preoperative prophylaxis.

Anti-Bacterial Agents↗

Mathematical neuroscience: from neurons to circuits to systems.

Applications of mathematics and computational techniques to our understanding of neuronal systems are provided. Reduction of membrane models to simplified canonical models demonstrates how neuronal spike-time statistics follow from simple properties of neurons. Averaging over space allows one to derive a simple model for the whisker barrel circuit and use this to explain and suggest several experiments. Spatio-temporal pattern formation methods are applied to explain the patterns seen in the early stages of drug-induced visual hallucinations.

Action Potentials↗