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Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions.

MOTIVATION: Polymorphisms in human genes are being described in remarkable numbers. Determining which polymorphisms and which environmental factors are associated with common, complex diseases has become a daunting task. This is partly because the effect of any single genetic variation will likely be dependent on other genetic variations (gene-gene interaction or epistasis) and environmental factors (gene-environment interaction). Detecting and characterizing interactions among multiple factors is both a statistical and a computational challenge. To address this problem, we have developed a multifactor dimensionality reduction (MDR) method for collapsing high-dimensional genetic data into a single dimension thus permitting interactions to be detected in relatively small sample sizes. In this paper, we describe the MDR approach and an MDR software package. RESULTS: We developed a program that integrates MDR with a cross-validation strategy for estimating the classification and prediction error of multifactor models. The software can be used to analyze interactions among 2-15 genetic and/or environmental factors. The dataset may contain up to 500 total variables and a maximum of 4000 study subjects. AVAILABILITY: Information on obtaining the executable code, example data, example analysis, and documentation is available upon request. SUPPLEMENTARY INFORMATION: All supplementary information can be found at http://phg.mc.vanderbilt.edu/Software/MDR.

Algorithms↗

Episodes of care: theoretical frameworks versus current operational realities.

BACKGROUND: Fundamental changes in the structure of the health care industry have stimulated the need for improved definitions of output and for better methods of organizing utilization data into appropriate units. Although the "episode of care" concept has existed since the 1960s, its recognition as integral to the management of health care cost and utilization is relatively recent. Conceptually, episodes of care represent a meaningful unit of analysis for assessing the full range of primary and specialty services provided in treating a particular health problem. Proprietary episode software grouper products are currently being used by health care organizations for the purposes of provider profiling, clinical benchmarking, disease management, and quality measurement. DESCRIPTION OF EPISODE GROUPER SOFTWARE PRODUCTS: Four episode grouper products are described that use a computerized approach for developing episodes of care from administrative data. They are compared on several characteristics, including purpose, case-mix adjustment, comprehensiveness, and clinical flexibility. Their differences in episode construction, such as how the start points and endpoints of an episode are defined, are also delineated. CONCLUSIONS: Episode groupers are critical to the analysis of health care delivery, since they focus on the entire process of care. Although all the groupers reviewed have many strengths, much developmental work still needs to occur in order to standardize the measurement and operationalization of episodes of care as units of analysis. Furthermore, until the data sources used are more valid and reliable, they will at best remain gross screening measures of quality.

Benchmarking↗

A fast, independent dose check of HDR plans.

High dose rate (HDR) brachytherapy often involves optimization routines to calculate the dwell times and positions of a radioactive source along specified applicator paths. These routines optimize the dwells in such a way as to deliver the prescribed dose at one or more points while satisfying various constraints. The importance of independently verifying the doses calculated by the optimization software prior to treatment delivery has been recognized in various works, and is a requirement of various regulatory agencies. Most previous methods are specific to particular treatment configurations, or require a full replanning of the case. In this work we describe an in-house software which provides an independent verification of dose calculations in less than 3 min, which adds negligible additional waiting time for the patient, regardless of the number of applicators, paths of the applicators, or complexity of the dwell times and positions. In order to verify errors which may occur between the planning and delivery stages, the verification code directly uses the treatment file used to control the HDR afterloader to compute the dose. Since this file references the source positions in the frame of reference of the catheters, an algorithm is described to convert these positions to Cartesian coordinates. We validate the code for various arbitrary cases ranging from a single catheter to complex multicatheter plans, and show results for various clinical plans. The maximum discrepancy observed for these clinical plans is 2%.

Brachytherapy↗

Validation of a customized LIMS.

The advantages of customized Laboratory Information Management's Systems (LIMS) are their focus on the special aspects of their users' needs. Differences in the research and development or production chain in the individual organizations lead to an increase of interest in customized systems. Usually, also for customized systems, the core software is commercially available. The individual application modules as the Customized part of the LIMS are the most critical elements within the validation process. The topic of this paper is to give an example of the validation of a customized analytical LIMS. Validation of complex computerized systems guarantees the intended use and is therefore an unavoidable requirement of authorities. The audit of the supplier of the individual programmed modules, the user requirement specifications and the acceptance testing and results, respectively, on the software are of special interest within a customized LIMS. The hardware suitability and the principal processing routines are also a very important part of the whole validation process, but they will not be discussed in detail in this paper.

Clinical Laboratory Information Systems↗

A microcomputer-based clinical trial database incorporated with an 'audit trail' for correction process.

Multicenter clinical trials usually involve several hundred research variables with tens of thousands of records and require mainframe computers for processing. Because of recent advances in hardware and software, it has become possible to support data management and statistical analysis for a complex research project totally on a microcomputer. The Veterans Administration Cooperative Studies Program Coordinating Center (CSPCC) in Hines, IL, U.S.A. has successfully implemented three studies employing the SIR/PC Database Management System (DBMS) on an IBM PC AT. The CSPCC DBMS was designed with a method of verifying data and of updating the database, that leaves a more detailed 'audit trial' of the original data and subsequent modifications than provided by the SIR audit trail facility. Data validation can be done at any time throughout the study to facilitate error identification as early as possible in the data handling process. DBMS operation and maintenance are automated by a system of menus. The utility programs are prestored in a procedure file to optimize performance. The simple design speeds implementation and also reduces the cost of development.

Clinical Trials as Topic↗

The classification of violence risk.

The Classification of Violence Risk (COVR) is an interactive software program designed to estimate the risk that a person hospitalized for mental disorder will be violent to others. The software leads the evaluator through a chart review and a brief interview with the patient. At the end of this interview, the software generates a report that contains a statistically valid estimate of the patient's violence risk-ranging from a 1% to a 76% likelihood of violence-including the confidence interval for that estimate, and a list of the risk factors that the program took into account to produce the estimate. In this article, the development of the COVR software is described and several issues that arise in its administration are discussed.

Antisocial Personality Disorder↗

Evaluation of educational software.

Evaluation is an important component of developing educational software. Ideally, such evaluation quantifies and qualifies the effects of a new educational intervention on the learning process and outcomes. Conducting meaningful and rigorous educational evaluation is difficult, however. Challenges include defining and measuring educational outcomes, accounting for media effects, coping with practical problems in designing studies, and asking the right research questions. Practical considerations that make the design of evaluation studies difficult include confounding, potentially small effect sizes, contamination effects, and ethics. Two distinct approaches to evaluation are objectivist and subjectivist. These two complement each other in describing the whole range of effects a new educational program can have. Objectivist demonstration studies should be preceded by measurement studies that assess the reliability and validity of the evaluation instrument(s) used. Many evaluation studies compare the performance of learners who are exposed to either the new program or a more traditional approach. However, this method is problematic because test or exam performance is often a weak indicator of competence and may fail to capture important nuances in outcomes. Subjectivist studies are more qualitative in nature and may provide insights complementary to those gained with objectivist studies. Several published examples are used in this article to illustrate different evaluation methods. Readers are encouraged to contemplate a wide range of evaluation study designs and explore increasingly complex questions when evaluating educational software.

Computer Simulation↗

Human urine proteome analysis by three separation approaches.

The urinary proteome is known to be a valuable field of study related to organ functions. There have been several extensive urine proteome studies. However, the overlapping rate among different studies is relatively low. Whether the low overlapping rate was caused by different sample sources, preparation, separation and identification methods is unknown. Moreover, low molecular mass (<10 kDa) proteins have not been studied extensively. In this report, male and female pooled urine samples were collected from healthy volunteers. The urinary proteins were acetone precipitated, separated and identified by three approaches, 1-DE plus 1-D LC/MS/MS, direct 1-D LC/MS/MS and 2-D LC/MS/MS. 1-D tricine gels were used to separate low molecular mass proteins. The tandem mass spectra of positive identifications were quality controlled both by manual validation and using advanced mass spectrum scanner software. A total of 226 urinary proteins were identified; 171 proteins were identified by proteomics approach for the first time, including 4 male-specific proteins. Twelve low molecular mass proteins were identified. Most urinary proteins had a molecular mass between 30 and 60 kDa and a pI between 4 and 10. The apparent molecular masses of many proteins were different from theoretical ones, which indicated their post-translational modification and degradation. The effects of sample preparation, separation and identification methods on the overlapping rate of different experiments are discussed.

Adult↗

[Computer assisted methods in reconstructive and function-preserving orbital surgery. New capabilities of computer assisted preoperative surgical planning (CAPP) and computer assisted surgery (CAS)].

BACKGROUND: Orbital reconstruction after tumor or trauma makes high demands on the surgeon when restoring the optic axis and cosmetic features. Computer-assisted preoperative planning surgery (CAPP) and computer-assisted surgery (CAS) allow calculation of the form of the orbital cavity to be reconstructed preoperatively as well as the process of its realization intraoperatively. METHODS: We developed new planning software methods for this surgical procedure. For validation the deviation of accuracy was assessed between the virtual and the real model in eight patients with surgical reconstruction of the orbit. RESULTS: The check of accuracy of the reconstructions compared to the planning of the surgery by fusion of preoperative and postoperative data resulted in a mean deviation of 1.74 mm. The volumetric measurements presented a mean deviation of 0.2 cm(3) with an accuracy of >99%. The accuracy of linear measurements with the techniques of image fusion of the "feature-based" method was 0.38 mm and thus close to the technical threshold of effective data accuracy of 0.35 mm. The enophthalmus could be assessed more objectively with this method compared to using the Hertel index. CONCLUSIONS: CAPP and CAS are helpful in reconstructive orbital surgery to verify the position of the optic axis and the cosmetic result intraoperatively.

Adult↗

Lay beliefs about hepatitis among North American Chinese: implications for hepatitis prevention.

The objective was to learn about the hepatitis prevention behavior of relatively unacculturated North American Chinese adults, along with their knowledge, beliefs, and perceptions with regard to hepatitis, screening, and vaccination. Forty Chinese men and women, aged 18-64, were recruited from immigrant communities in Seattle, Washington, and Vancouver, British Columbia. Semi-structured interviews (Cantonese or Mandarin) were audiotaped, translated, transcribed verbatim, and coded. Open coding, axial coding, constant comparison methods, and QSR NUD*IST 5 software was used for analysis. Findings were validated using eight focus groups. Findings indicated that many interviewees lack accurate knowledge with regard to hepatitis, often confusing the different types. Perceived causes of hepatitis included potentially harmful food (e.g., fried foods or potentially contaminated foods), alcohol, contact with infected individuals, stress, and inadequate rest. Preventive strategies associated with Chinese health beliefs included the use of Chinese herbal medicine, maintaining a stress-free mind, strengthening the body's natural defenses, and getting enough sleep. Other preventive strategies were the practice of good hygiene, vaccination, and the avoidance of contact with infected persons. Vaccination was not seen as primary, as 65% of those who had heard of hepatitis vaccination did not cite it as a means for hepatitis prevention until asked. Also, participants lacked information about the types and purposes of hepatitis vaccination and were worried about side effects. In conclusion, any attempt to promote hepatitis testing and vaccination among the North American Chinese should take traditional beliefs and practices into consideration.

Adolescent↗

An automated tracking system for Caenorhabditis elegans locomotor behavior and circadian studies application.

Automation of simple behavioral patterns, such as locomotor activity, is fundamental for pharmacological and genetic screening studies. Recently, circadian behaviors in locomotor activity and stress responses were reported in the nematode Caenorhabditis elegans, a well-known model in genetics and developmental studies. Here we present a new method for long-term recordings of C. elegans (as well as other similar-sized animals) locomotor activity based on an infrared microbeam scattering. Individual nematodes were cultured in a 96-well microtiter plate; we tested L15, CeMM and E. coli liquid cultures in long-term activity tracking experiments, and found CeMM to be the optimal medium. Treatment with 0.2% azide caused an immediate decrease in locomotor activity as recorded with our system. In addition to the validation of the method (including hardware and software details), we report its application in chronobiological studies. Circadian rhythms in animals entrained to light-dark and constant dark conditions (n=48 and 96 worms, respectively) at 16 degrees C, were analyzed by LS periodograms. We obtained a 24.2+/-0.44 h period (52% of significantly rhythmic animals) in LD, and a 23.1+/-0.40 h period (37.5% of significantly rhythmic animals) under DD. The system is automateable using microcontrollers, of low-cost construction and highly reproducible.

Animals↗

Automation of NMR structure determination of proteins.

The automation of protein structure determination using NMR is coming of age. The tedious processes of resonance assignment, followed by assignment of NOE (nuclear Overhauser enhancement) interactions (now intertwined with structure calculation), assembly of input files for structure calculation, intermediate analyses of incorrect assignments and bad input data, and finally structure validation are all being automated with sophisticated software tools. The robustness of the different approaches continues to deal with problems of completeness and uniqueness; nevertheless, the future is very bright for automation of NMR structure generation to approach the levels found in X-ray crystallography. Currently, near completely automated structure determination is possible for small proteins, and the prospect for medium-sized and large proteins is good.

Automation↗

Recovery, visualization, and analysis of actin and tubulin polymer flow in live cells: a fluorescent speckle microscopy study.

Fluorescent speckle microscopy (FSM) is becoming the technique of choice for analyzing in vivo the dynamics of polymer assemblies, such as the cytoskeleton. The massive amount of data produced by this method calls for computational approaches to recover the quantities of interest; namely, the polymerization and depolymerization activities and the motions undergone by the cytoskeleton over time. Attempts toward this goal have been hampered by the limited signal-to-noise ratio of typical FSM data, by the constant appearance and disappearance of speckles due to polymer turnover, and by the presence of flow singularities characteristic of many cytoskeletal polymer assemblies. To deal with these problems, we present a particle-based method for tracking fluorescent speckles in time-lapse FSM image series, based on ideas from operational research and graph theory. Our software delivers the displacements of thousands of speckles between consecutive frames, taking into account that speckles may appear and disappear. In this article we exploit this information to recover the speckle flow field. First, the software is tested on synthetic data to validate our methods. We then apply it to mapping filamentous actin retrograde flow at the front edge of migrating newt lung epithelial cells. Our results confirm findings from previously published kymograph analyses and manual tracking of such FSM data and illustrate the power of automated tracking for generating complete and quantitative flow measurements. Third, we analyze microtubule poleward flux in mitotic metaphase spindles assembled in Xenopus egg extracts, bringing new insight into the dynamics of microtubule assemblies in this system.

Actins↗

Diagnostic tools to determine the quality of "transparent" regression-based QSARs: the "modelling power" plot.

A bivariate plot is presented for comparing two or more QSAR models. It is based on two new statistics associated with a regression model, the "descriptive power" (Dp), which is estimated through the relative uncertainty of model coefficients, and the "predictive power" (Pp), which is estimated through both the fitted and cross-validated explained variance of the response variable (i.e., biological activity). An algorithm was developed for performing equivalent multiple linear regression and partial-least-squares calculations. The results were validated by comparison with widely accepted commercial software. Dp and Pp statistics are defined to vary from 0 to 100%, so the modeler has a intuitive impression of the descriptive (i.e., global importance of the selected descriptors) and predictive (i.e., possibility of performing QSAR or just SAR estimations) power. These statistics represent a point in the Dp versus Pp "modelling power" plot, which facilitates visual multiple models comparison, but also could be used to substitute classical statistics and could even be combined to obtain a unique parameter to define (or compare) the model's quality.

Animals↗

Computerized morphometry and three-dimensional image reconstruction in the evaluation of scalp biopsy from patients with non-cicatricial alopecias.

BACKGROUND: A major challenge in the histopathological examination of scalp biopsies is to perform an adequate evaluation of all the hair follicles present in the tissue. Transverse sectioning is currently the preferred technique to demonstrate every follicular structure in a punch biopsy specimen, although diagnostic accuracy is dependent on subjective evaluation of follicular morphology and hair size. OBJECTIVES: To determine if computer-based morphometry and three-dimensional (3D) image reconstruction software can be used to evaluate scalp biopsies from patients with non-cicatricial alopecias. METHODS: Nine 4-mm scalp punches were taken from nine patients with noncicatricial alopecias and step-sectioned transversely at 0.1-mm intervals from the epidermal surface to the subcutaneous fat. Each tissue section was then digitized and analysed using morphometric and 3D image reconstruction software. Morphometric data and 3D images were collated with clinical and conventional light microscopic diagnoses, as well as follow-up information. RESULTS: In four of the nine patients, results of morphometric analysis concurred with conventional clinicopathological diagnoses. In the remaining five patients, morphometry revealed a lower telogen count in one patient and higher telogen count in four patients. One of the four patients with a higher telogen count also had a low mean hair diameter and miniaturized anagen follicles in the 3D image that were suggestive of early androgenetic alopecia (AGA). 3D virtual microscopic imagery allowed the direct visualization of colour-coded, scaled hair follicles which demonstrated characteristic changes in alopecia areata, AGA and telogen effluvium. CONCLUSIONS: Our study demonstrated the feasibility of using morphometric and 3D reconstruction software to evaluate scalp biopsies. With further validation, this technique may prove to be more sensitive to detect subtle quantitative and qualitative follicular changes in non-cicatricial alopecias.

Adolescent↗

Clustering-based approaches to discovering and visualising microarray data patterns.

This article focuses on clustering techniques for the analysis of microarray data and discusses contributions and applications for the implementation of intelligent diagnostic systems and therapy design studies. Approaches to validating and visualising expression clustering results and software and other relevant resources to support clustering-based analyses are reviewed. Finally, this paper addresses current limitations and problems that need to be investigated for the development of an advanced generation of pattern discovery tools.

Multigene Family↗

How reliable is the Bispectral Index in critically ill patients? A prospective, comparative, single-blinded observer study.

OBJECTIVE: To establish a correlation between a reliable subjective measure, the Sedation-Agitation Scale (SAS), and an objective tool, the Bispectral Index (BIS), for monitoring critically ill patients with a decreased level of consciousness. DESIGN: Prospective, comparative, single-blinded observer study. SETTING: Surgical and medical intensive care units of the Tufts-New England Medical Center, a 349-bed tertiary care, academic medical center. PATIENTS: A convenience sample of 20 adult, critically ill patients with a decreased level of consciousness. The data from one patient were excluded because the patient did not meet inclusion criteria. MEASUREMENTS AND MAIN RESULTS: Patients were prospectively evaluated by a blinded observer using the SAS to subjectively determine their level of consciousness. Sedation levels varied from unarousable (SAS score of 1), to very sedated (SAS score of 2), to mildly sedated (SAS score of 3). Simultaneously, the patients were continuously monitored for 4-6 hrs with the BIS device. There was wide variability in BIS scores for any given level of consciousness as compared with the SAS. Unarousable patients had BIS scores ranging from 23 to 97, with a median score of 50 and an interquartile range of 24. Very sedated patients had BIS scores ranging from 35 to 98, with a median score of 68 and an interquartile range of 36. Mildly sedated patients had BIS scores ranging from 67 to 91, with a median score of 76 and an interquartile range of 8. Overall, there was a less than satisfactory correlation between BIS values and SAS scores (r =.36, p <.001). However, the correlation improved with subgroup analysis when BIS values associated with excessive muscle movement were excluded (r =.50, p <.001). CONCLUSIONS: The correlation between SAS and BIS scores was suboptimal and inconsistent in a heterogeneous group of critically ill patients. The generation of BIS hardware and software, studied herein, is neither reliable nor valid for routinely monitoring the level of consciousness in the critically ill patient. Excessive muscle movement by the patient is an important and spurious influence on BIS values and seriously undermines BIS reliability.

Procedural Sedation↗

Normal esophageal body function: a study using ambulatory esophageal manometry.

OBJECTIVE: The objective of this study was to establish normative ambulatory manometric data for contractions and contraction propagation in three levels of the esophagus. METHODS: Twenty-five healthy volunteers underwent simultaneous ambulatory 24 h manometry. Concomitant 24 h pH studies were performed to exclude the presence of increased esophageal acid exposure. Pressures were recorded over a complete circadian cycle while patients continued with their normal lifestyles including eating and sleeping. Data were analyzed with a software program that was previously modified and validated and that enables quantitation of contractions in terms of efficacy. RESULTS: The frequency of contractions was lowest during sleep, was increased when awake, and was highest during meals. Contraction amplitude increased during meals, providing a greater propulsive force for bolus transport. Similarly, the prevalence of peristaltic waves varied according to different physiologic states, ie., while eating, upright, awake, and sleeping. An increased amplitude and prevalence of peristalsis resulted in an increase in manometric efficacy during meals. CONCLUSIONS: This study provides normative data for ambulatory manometry for comparison when studying patients with disease.

Adult↗