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PubMed1998

Method and computer program for controlling the family-wise alpha rate in gene association studies involving multiple phenotypes.

Multiple significance testing involving multiple phenotypes is not uncommon in the context of gene association studies but has remained largely unaddressed. If no adjustment is made for the multiple tests conducted, the type I error probability will exceed the nominal (per test) alpha level. Nevertheless, many investigators do not implement such adjustments. This may, in part, be because most available methods for adjusting the alpha rate either: 1) do not take the correlation structure among the variables into account and, therefore, tend to be overly stringent; or 2) do not allow statements to be made about specific variables but only about multivariate composites of variables. In this paper we develop a simulation-based method and computer program that holds the actual alpha rate to the nominal alpha rate but takes the correlation structure into account. We show that this method is more powerful than several common alternative approaches and that this power advantage increases as the number of variables and their intercorrelations increase. The method appears robust to marked non-normality and variance heterogeneity even with unequal numbers of subjects in each group. The fact that gene association studies with biallelic loci will have (at most) three groups (i.e., AA, Aa, aa) implies by the closure principle that, after detection of a significant result for a specific variable, pairwise comparisons for that variable can be conducted without further adjustment of the alpha level.

Analysis of Variance↗
PubMed1997

Implications of alternative methods of computing blood pressure means.

BACKGROUND: Blood pressure measures are traditionally averaged to compute a level across a period. There are, however, two ways of calculating such means: by assigning equal weights to each time interval or to each heartbeat. The former method is used commonly with intermittent measures, the latter with continuous measurements, though either can be calculated with either monitoring technique. For periods during which there is substantial variability in the cardiovascular levels, and in which the pulse is correlated with the blood pressure, the two techniques will produce different results. METHODS: We illustrated the difference between the two techniques by calculating mean blood pressure levels during two episodes, with the heart rate and blood pressure monitored continuously using the Finapres 2300 blood pressure monitor. RESULTS: During the first episode, there was dramatic variability in heart rate and blood pressure. The pulse-based calculations, which give greater weight to the periods during which the pulse is elevated, gave means for the systolic and diastolic blood pressures substantially higher than those obtained using time-based methods. During the second episode, both the heart rate and the blood pressure were stable, and we observed no difference between the results from the two methods of calculating the means. CONCLUSIONS: Because there are theoretical justifications for both methods of computation, and they can produce different results, it is important that researchers attend to the difference, and describe the technique used when presenting results.

Journal Article↗
PubMed1989

The global extrapolation of numerical methods for computing concentration profiles in percutaneous drug absorption.

A family of numerical methods is developed and analyzed for the numerical solution of the parabolic partial differential equation together with the associated initial and boundary conditions, which arise in a mathematical model of the transient stage of percutaneous drug absorption. Two global extrapolation procedures are described, the first in time only, the second in both space and time, for improving the accuracy of the computed concentration profiles. The behaviours of two members of the family of methods, before and after extrapolation, are examined by repeating a number of experiments reported in the literature. Modifications to the algorithms, which are necessary in computing concentration profiles after the ointment is removed at the steady state, are outlined.

Administration, Cutaneous↗
PubMed2025

Absolute copy number aware CNV calling of sub-megabase segments in ultra-low coverage single-cell DNA sequencing data.

Recent advances in ultra-low coverage whole-genome sequencing (WGS) of single cells have enabled detailed analysis of copy number variation at a throughput approaching that of single-cell RNA sequencing. However, downstream computational methods have not seen comparable advances and are largely adaptations of deep sequencing methodology with reduced precision. Here, we present ASCENT, a computational method built to take full advantage of modern direct tagmentation-based WGS at ultra-low depth. Using joint segmentation with high-resolution bins, we accurately detect small segments, achieving accurate copy number profiles even at 100 000 reads per cell. ASCENT implements true absolute copy state inference for single cells, based on statistical modeling of coverage rather than comparison to a reference, while taking variable segment copy state into account. Further, ASCENT implements per-segment copy-neutral loss of heterozygosity (LOH) calling without the need for non-tumor or bulk WGS reference. When applied to a pediatric B-ALL sample, ASCENT finds copy-neutral LOH in a small segment and a minor subclone defined by breakpoints missed in bulk WGS. Thus, by applying appropriate computational methods, single-cell WGS provides clear advantages over bulk, even at a relatively low cell number and sequencing depth.

DNA Copy Number Variations↗
PubMed1999

A computer-based method for continuous single pulse analysis of intracranial pressure waves.

INTRODUCTION: The single pulse analysis of intracranial pressure waves provides valuable information about the autoregulative processes after head injury. This method has not been used for routine clinical assessment as yet. Current methods for evaluation of intracranial pressure waves are based on spectral analysis or related techniques. This imposes restrictions on the wave sequences available for the investigation of ICP attributes. Therefore, we have developed a computer-based method, which enables continuous analysis of each pulse of the ICP wave, in any clinical setting. METHOD: Firstly, the raw data of the ICP wave is continuously recorded by the Multifunctional Anaesthetic Record System (MARS, Hewlett Packard). The recorded data is then subjected to single pulse wave analysis by our software. Each single pulse is identified by the algorithm. The maximum, minimum and mean value, as well as amplitude and gradient are calculated in each pulse pressure. All conceivable correlations of the listed parameters can be examined. RESULTS: We applied our software in 9 cases with head injury and evaluated the measurements over 59 days (1400 h). More than 7 million single pulse pressures have been analyzed off-line. The software proved to be accurate and easy to apply. It was possible to calculate correlations between the different wave attributes on a broad basis of data. Parameters of special clinical interest were the amplitude of the single pulse pressure and the gradient. CONCLUSION: This method is an improvement on ICP single pulse pressure analysis and facilitates its clinical application. It creates the possibility for continuous long-term analysis of the ICP wave attributes under any clinical condition without loss of data. There are indications that the amplitude and the gradient of the ICP pulse pressure could provide valuable additional information for clinical assessment. However, further evaluation is required.

Craniocerebral Trauma↗
PubMed1992

A computer-assisted method for making linear radiographic measurements using stored regions of interest.

Accurate detection of changes in alveolar bone height requires radiographic measuring methods with a reliability of standard deviation (SD) of 0.15 mm or better. No periodontal digital imaging system has reached this reliability, although 3 analogue methods have achieved this goal. However, existing linear methods are time-consuming, difficult to use, unsuitable for measuring all possible (unsharp) anatomical sites and do not provide a confidence estimate for sites of change observed in serial standardized films. A rapid computer-assisted method using stored image regions of interest (ROI) has been developed which allows retest measurements for all possible sites and automatically calculates a 90%, 95%, 98%, or 99% confidence threshold value, derived from duplicate measurement variation, for sites of apparent crest height change. 28 examiners, with minimal training in operating the system, measured 14 different cement-enamel junction to crest height distances from a standard bitewing image, with and without the ROI method. The measurements were repeated 4 weeks later. 13/14 sites achieved an intra-examiner SD threshold of less than or equal to 0.15 mm with the ROI method but 0/14 without. A higher inter-examiner SD threshold of less than or equal to 0.22 mm was achieved for 13/14 sites using ROI and 0/14 without (p less than 0.001). The measurement of crest height changes in a region of previous severe vertical bone loss is demonstrated using serial films. The potential for using trabecular bone patterns as reference sites in regions where traditional measurement points are absent is demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Alveolar Bone Loss↗
PubMed2005

Quantifying motion in video recordings of neonatal seizures by regularized optical flow methods.

This paper presents the development of regularized optical flow computation methods and an evaluation of their performance in the extraction of quantitative motion information from video recordings of neonatal seizures. A general formulation of optical flow computation is presented and a mathematical framework for the development of practical tools for computing optical flow is outlined. In addition, this paper proposes an alternative formulation of the optical flow problem that relies on a discrete approximation of a family of quadratic functionals. These regularized optical flow computation methods are used to extract motion strength signals from video recordings of neonatal seizures.

Algorithms↗
PubMed2002

Adaptive constraints and the phylogenetic comparative method: a computer simulation test.

Recently, the utility of modern phylogenetic comparative methods (PCMs) has been questioned because of the seemingly restrictive assumptions required by these methods. Although most comparative analyses involve traits thought to be undergoing natural or sexual selection, most PCMs require an assumption that the traits be evolving by less directed random processes, such as Brownian motion (BM). In this study, we use computer simulation to generate data under more realistic evolutionary scenarios and consider the statistical abilities of a variety of PCMs to estimate correlation coefficients from these data. We found that correlations estimated without taking phylogeny into account were often quite poor and never substantially better than those produced by the other tested methods. In contrast, most PCMs performed quite well even when their assumptions were violated. Felsenstein's independent contrasts (FIC) method gave the best performance in many cases, even when weak constraints had been acting throughout phenotypic evolution. When strong constraints acted in opposition to variance-generating (i.e., BM) forces, however, FIC correlation coefficients were biased in the direction of those BM forces. In most cases, all other PCMs tested (phylogenetic generalized least squares, phylogenetic mixed model, spatial autoregression, and phylogenetic eigenvector regression) yielded good statistical performance, regardless of the details of the evolutionary model used to generate the data. Actual parameter estimates given by different PCMs for each dataset, however, were occasionally very different from one another, suggesting that the choice among them should depend on the types of traits and evolutionary processes being considered.

Adaptation, Physiological↗
PubMed1996

Computer-assisted clinimetric tool for the study of facial expression: a pilot validity study.

Clinimetrics is the measurement of clinical phenomena; more specifically, it is mensuration, the act of acquiring and labeling basic raw data that is used to describe or measure symptoms, signs, and other distinctly clinical phenomena. Over the last 5 years, a new computer method for measuring facial expression has been developed. Refinement and validation of this technique are necessary before clinical applications are appropriate. Four hundred fifty data points from two human observers and the computed method were compared with one another by using indices of location, dispersion, and association within the framework of the logical construct of validity. These results suggest that the computed method is valid. This new method may be nearly ready for clinical applications as a primary or adjunctive clinimetric tool.

Adult↗
PubMed1993

Multiple-site titration and molecular modeling: two rapid methods for computing energies and forces for ionizable groups in proteins.

Computer models of proteins frequently treat the energies and forces associated with ionizable groups as if they were purely electrostatic. This paper examines the validity of the purely electrostatic approach, and concludes that significant errors in energies can result from the neglect of ionization changes. However, a complete treatment of ionizable groups presents substantial computational obstacles, because of the large number of ionization states which must be examined in systems having multiple interacting titratable groups. In order to address this problem, two novel methods for treating the energetics and forces associated with ionizable groups with a minimum of computer time have been developed. The most rapid method yields approximate energies by computing the free energy of a single highly occupied ionization state. The second method separates ionizable groups into clusters, and treats intracluster interactions exactly, but intercluster interactions approximately. This method yields both accurate energies and fractional charges. Good results are obtained in tests of both methods on proteins having has many as 123 ionizable groups. The more rapid method requires computer times of 0.01 to 0.34 sec, while the more accurate method requires 0.7 to 15 sec. These methods may be fast enough to permit the incorporation of ionization effects in iterative computations, such as energy minimizations and conformational searches.

Animals↗
PubMed1977

Computer-assisted method for multi-exponential curve fitting for determining cerebral blood flow.

A computer program has been developed for use in determining cerebral blood flow using an inert radioactive gas. The basic algorithm involves the determination of multiple exponential coefficients from the complex concentration-time function. The exponential coefficients are determined by 'peeling' away slower exponentials complex function one at a time. The procedure involves the use of a small laboratory computer in the interactive graphics mode. The method is currently in use analyzing data in a cerebral vascular research laboratory.

Animals↗
PubMed2004

Predicted 3-D structures for mouse I7 and rat I7 olfactory receptors and comparison of predicted odor recognition profiles with experiment.

The first step in the perception of an odor is the activation of one or more olfactory receptors (ORs) following binding of the odorant molecule to the OR. In order to initiate the process of determining how the molecular level receptor-odorant interactions are related to odor perception, we used the MembStruk computational method to predict the three-dimensional (3-D) structure of the I7 OR for both mouse and rat. We then used the HierDock ligand docking computational method to predict the binding site and binding energy for the library of 56 odorants to these receptors for which experiment response data are now available. We find that the predicted 3-D structures of the mouse and rat I7 OR lead to predictions of odorant binding that are in good agreement with the experimental results, thus validating the accuracy of both the 3-D structure and the predicted binding site. In particular we predict that heptanal and octanal both bind strongly to both mouse and rat I7 ORs, which conflicts with the older literature but agrees with recent experiments. To provide the basis of additional validations of our 3-D structures, we also report the odorant binding site for a new odorant (8-hydroxy-octanal) with a novel functionality designed to bind strongly to mouse I7. Such validated computational methods should be very useful in predicting the structure and function of many other ORs.

Amino Acid Sequence↗
PubMedDate not supplied

A rapid method for computing the inverse of the gametic covariance matrix between relatives for a marked quantitative trait locus.

The inverse of the gametic covariance matrix between relatives, G(-1), for a marked quantitative trait locus (QTL) is required in best linear unbiased prediction (BLUP) of breeding values if marker data are available on a QTL. A rapid method for computing the inverse of a gametic relationship matrix for a marked QTL without building G itself is presented. The algorithm is particularly useful due to the approach taken in computing inbreeding coefficients by having to compute only few elements of G. Numerical techniques for determining, storing, and computing the required elements of G and the nonzero elements of the inverse are discussed. We show that the subset of G required for computing the inbreeding coefficients and hence the inverse is a tiny proportion of the whole matrix and can be easily stored in computer memory using sparse matrix storage techniques. We also introduce an algorithm to determine the maximum set of nonzero elements that can be found in G(-1) and a strategy to efficiently store and access them. Finally, we demonstrate that the inverse can be efficiently built using the present techniques for very large and inbred populations.

Algorithms↗
PubMed1991

A random walk method for computing genetic location scores.

Calculation of location scores is one of the most computationally intensive tasks in modern genetics. Since these scores are crucial in placing disease loci on marker maps, there is ample incentive to pursue such calculations with large numbers of markers. However, in contrast to the simple, standardized pedigrees used in making marker maps, disease pedigrees are often graphically complex and sparsely phenotyped. These complications can present insuperable barriers to exact likelihood calculations with more than a few markers simultaneously. To overcome these barriers we introduce in the present paper a random walk method for computing approximate location scores with large numbers of biallelic markers. Sufficient mathematical theory is developed to explain the method. Feasibility is checked by small-scale simulations for two applications permitting exact calculation of location scores.

Chromosome Walking↗
PubMed2007

A comparison of methods to compute the potential of mean force.

Most processes occurring in a system are determined by the relative free energy between two or more states because the free energy is a measure of the probability of finding the system in a given state. When the two states of interest are connected by a pathway, usually called reaction coordinate, along which the free-energy profile is determined, this profile or potential of mean force (PMF) will also yield the relative free energy of the two states. Twelve different methods to compute a PMF are reviewed and compared, with regard to their precision, for a system consisting of a pair of methane molecules in aqueous solution. We analyze all combinations of the type of sampling (unbiased, umbrella-biased or constraint-biased), how to compute free energies (from density of states or force averaging) and the type of coordinate system (internal or Cartesian) used for the PMF degree of freedom. The method of choice is constraint-bias simulation combined with force averaging for either an internal or a Cartesian PMF degree of freedom.

Journal Article↗
PubMed2005

Social dominance orientation, prejudice, and discrimination: a new computer-based method for studying discriminatory behaviors.

A number of studies have shown that the scale of social dominance orientation (SDO), used to measure the degree of preference for inequality among social groups, is a predictive measure of social and political attitudes toward stigmatized outgroups. However, the relationship between SDO and discrimination has received little attention. The main goal of this study was to assess the validity of a new computer-based method used to measure discriminatory behaviors in a laboratory setting. An additional goal was to test the mediating role of prejudice in the relation between SDO and discrimination. The results provide a first validation of this new method and demonstrate that the effect of SDO on discrimination is mediated by prejudice.

Adolescent↗
PubMed1979

Quantification of myocardial ischemia and infarction with 201thallium scintigraphy.

A quantitative method for the analysis of 201thallium myocardial scintigrams, developed in an experimental infarcted dog heart model, has been compared with two nonquantitative methods for interpretation of stress myocardial scintigrams in two groups of patients studied with coronary angiography: 11 with normal coronary arteries and 14 with coronary artery disease. Three independent observers interpreted scintigrams which were 1) not computer processed; 2) corrected for background activity in lungs and chest wall; and 3) processed by a computer method which uses a uniform threshold of counts determined from the dog model to define perfusion defects. Interobserver variability as well as sensitivity and specificity of detecting coronary disease were examined. In patients with coronary artery disease interobserver variability was improved by using the computer technique: observers agreed as to the existence of a perfusion defect in 93% of the scintigrams as compared to 55% and 81% for the unprocessed and background-subtracted images respectively. No false positive indications of coronary disease were obtained by any of the three techniques. Use of the computer method did not improve the sensitivity of detecting coronary disease, however--71% compared to 64% for unprocessed images and 79% for background-substracted images. The advantages of this quantitative computer method are increased consistency of interpretation and lack of false positive diagnoses of coronary disease. An improved sensitivity of detection may be gained by varying thallium count thresholds according to anatomic location in the heart.

Animals↗
PubMed2005

Review and evaluation of methods for computing confidence intervals for the ratio of two proportions and considerations for non-inferiority clinical trials.

This article reviews several methods for forming confidence intervals for a risk ratio of two independent binomial proportions (which are both less than 0.50) and evaluates their statistical performance. These methods include use of a Taylor Series expansion to estimate variance, solutions to a quadratic equation, and maximum likelihood methods. In addition, for improvement of the properties of the methods based on large sample approximations, situations where either binomial count was less than or equal to 3 were managed conservatively by having an exact confidence interval for the odds ratio become the confidence interval for its risk ratio counterpart. Methods were initially evaluated by computing confidence limits for certain cases. Second, simulations were used to identify the better methods for controlling the Type I error rate while maintaining power. Last, relationships between methods were evaluated by calculating the percent of disagreement in the decision made regarding non inferiority. Methods in the group using a Taylor Series expansion in variance estimation perform similarly to the Pearson method preferred in the literature. In addition, the group of methods using a Taylor Series expansion are most easily computed. Applications of these findings are discussed for ratios that arise in randomized clinical trials that are conducted to show noninferiority of a new medical product to a reference control. Consideration is given as well to sample size calculations for noninferiority clinical trials.

Chi-Square Distribution↗