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PubMed1995

Guess LOD approach: sufficient conditions for robustness.

Analysis of genetic linkage between a disease and a marker locus requires specifying a genetic model describing both the inheritance pattern and the gene frequencies of the marker and trait loci. Misspecification of the genetic model is likely for etiologically complex diseases. In previous work we have shown through analytic studies that misspecifying the genetic model for disease inheritance does not lead to excess false-positive evidence for genetic linkage provided the genetic marker alleles of all pedigree members are known, or can be inferred without bias from the data. Here, under various selection or ascertainment schemes we extend these previous results to situations in which the genetic model for the marker locus may be incorrect. We provide sufficient conditions for the asymptotic unbiased estimation of the recombination fraction under the null hypothesis of no linkage, and also conditions for the limiting distribution of the likelihood ratio test for no linkage to be chi-squared. Through simulation studies we document some situations under which asymptotic bias can result when the genetic model is misspecified. Among those situations under which an excess of false-positive evidence for genetic linkage can be generated, the most common is failure to provide accurate estimates of the marker allele frequencies. We show that in most cases false-positive evidence for genetic linkage is unlikely to result solely from the misspecification of the genetic model for disease or trait inheritance.

Genetic Linkage↗
PubMed1995

Robust multipoint linkage analysis: an extension of the Haseman-Elston method.

The use of multiple markers, rather than a single marker, can increase the likelihood of detecting linkage to a locus underlying a quantitative trait. In this paper, the Haseman-Elston sibpair method is extended to include information from multiple markers. The result is a linear regression of the squared pair trait difference on the jointly estimated proportions of genes shared identical by descent at the two closest flanking marker loci. The results strengthen the theoretical motivation for the interval mapping technique proposed by Fulker and Cardon [1994: Am J Hum Genet 54:1092-1103] and extend the method to include information from multiple markers, account for a trait dominance component, and examine the region just outside that defined by the markers. Simulations show that modest increases in power and substantial decreases in bias of parameter estimates are obtained when identity-by-descent probabilities are jointly estimated. The regression relationship is also developed for other types of relative pairs.

Chromosome Mapping↗
PubMed2001

A robust score test for linkage disequilibrium in general pedigrees.

Many family-based tests of linkage disequilibrium are not valid when related nuclear families from larger pedigrees are used, or when independent nuclear families with multiple cases are used. The Pedigree Disequilibrium Test (PDT) proposed by Martin et al. [Am J Hum Genet 67:146-54, 2000] avoids these problems. This paper sketches an extension of the PDT that can account for measured covariates. Where the PDT is based on allele-counting methods, this extension is based on conditional logistic regression. Versions of these statistics were used to test for association between disease and two known functional single nucleotide polymorphisms (SNPs) on gene 1 and gene 6 and one inert SNP on gene 7 in the first 25 replicates of the simulated population-isolate data. The new method was also used to test for linkage disequilibrium after correcting for the effect of the environmental factor E1. The PDT and the conditional logistic extension had similar power to detect the functional SNPs (100% for gene 1, approximately 50% for gene 6) and appropriate type I error rates for the inert SNP. Correcting for E1 slightly increased power to detect the association between gene 6 and disease.

Genetic Predisposition to Disease↗
PubMed2005

Robust estimation of critical values for genome scans to detect linkage.

Estimation of study specific critical values for linkage scans (suggestive and significant thresholds) is important to identify promising regions. In this report, I propose a fast and concrete recipe for finding study specific critical values. Previously, critical values were derived theoretically or empirically. Theoretically-derived values are often conservative due to their assumption of fully informative transmissions. Empirically-derived critical values are computer and skill intensive and may not even be computationally feasible for large pedigrees. In this report, I propose a method to estimate critical values for multipoint linkage analysis using standard, widely used statistical software. The proposed method estimates study-specific critical values by using Autoregressive (AR) models to estimate the correlation between standard normal statistics at adjacent map points and then use this correlation to estimate study-specific critical values. The AR-based method is evaluated using different family structures and density of markers, under both the null hypothesis of no linkage and the alternative hypothesis of linkage between marker and disease locus. Simulations results show the AR-based method accurately predicts critical values for a wide range of study designs.

Algorithms↗
PubMed2005

Fast robust subject-independent magnetoencephalographic source localization using an artificial neural network.

We describe a system that localizes a single dipole to reasonable accuracy from noisy magnetoencephalographic (MEG) measurements in real time. At its core is a multilayer perceptron (MLP) trained to map sensor signals and head position to dipole location. Including head position overcomes the previous need to retrain the MLP for each subject and session. The training dataset was generated by mapping randomly chosen dipoles and head positions through an analytic model and adding noise from real MEG recordings. After training, a localization took 0.7 ms with an average error of 0.90 cm. A few iterations of a Levenberg-Marquardt routine using the MLP output as its initial guess took 15 ms and improved accuracy to 0.53 cm, which approaches the natural limit on accuracy imposed by noise. We applied these methods to localize single dipole sources from MEG components isolated by blind source separation and compared the estimated locations to those generated by standard manually assisted commercial software.

Artifacts↗
PubMed2003

Assessing and comparing costs: how robust are the bootstrap and methods based on asymptotic normality?

This article addresses and challenges some common perceptions in the statistical assessment of costs and cost-effectiveness in health economics. Cost data typically exhibit highly skew distributions. Two techniques whose validity does not depend on any specific form of underlying distribution are the bootstrap and methods based on asymptotic normality of sample means. These methods are generally thought to be appropriate for the analysis of cost data. We argue that, even when these methods are technically valid, they may often lead to inefficient and even misleading inferences. It is important to apply methods that recognise the skewness in cost data. We further demonstrate that it may also be important to incorporate relevant prior information in a Bayesian analysis.

Bayes Theorem↗
PubMed2002

A robust method for detecting CHK2/RAD53 mutations in genomic DNA.

While screening for germline CHK2 mutations in cancer cases by heteroduplex CSGE, we observed that additional PCR fragments were generated from the 3' end region of the gene that includes exons 11-14. Direct sequencing of these fragments suggested that homologous loci (possibly pseudogenes) were concomitantly being amplified. Searches of public sequence databases showed that a number of areas of the genome show a high degree of homology to exons 10-14 of the CHK2 gene. The presence of these homologous regions means that standard screening methods for detecting mutations in CHK2, based on PCR of genomic DNA, are prone to error. To circumvent this problem, we have developed a strategy, based on long-range PCR, to screen the functional copy of CHK2. Using this approach it is possible to carry out a comprehensive mutational analysis of CHK2 from genomic DNA.

Base Sequence↗
PubMed2006

Ginkgo biloba: no robust effect on cognitive abilities or mood in healthy young or older adults.

Ginkgo biloba extracts are commonly used to prevent or treat memory problems but evidence on the efficacy of ginkgo is equivocal. In any case, the psychological locus of ginkgo's effects is unknown. A 12-week, double-blind, placebo-controlled study assessed effects of ginkgo (120 mg per day) on a wide range of cognitive abilities, executive function, attention and mood in 93 healthy older adults (55-79 years) and in 104 young adults (18-43 years). For the older adult sample, longer-term memory assessed by associational learning tasks showed improvement with ginkgo (d = 0.52, p = 0.04). There was no statistically significant difference on any other measure. For the young adult group no measure showed statistically significant effects of ginkgo enhancement. There were no side effects unequivocally attributable to treatment with ginkgo and those reported by participants in the ginkgo groups were mild and similar to those reported elsewhere.

Adolescent↗
PubMed2002

Folding funnels: the key to robust protein structure prediction.

Natural proteins fold because their free energy landscapes are funneled to their native states. The degree to which a model energy function for protein structure prediction can avoid the multiple minima problem and reliably yield at least low-resolution predictions is also dependent on the topography of the energy landscape. We show that the degree of funneling can be quantitatively expressed in terms of a few averaged properties of the landscape. This allows us to optimize simplified energy functions for protein structure prediction even in the absence of homology information. Here we outline the optimization procedure in the context of associative memory energy functions originally introduced for tertiary structure recognition and demonstrate that even partially funneled landscapes lead to qualitatively correct, low-resolution predictions.

Computational Biology↗
PubMed2004

An accurate and robust method for unsupervised assessment of abdominal fat by MRI.

PURPOSE: To describe and evaluate an automatic and unsupervised method for assessing the quantity and distribution of abdominal adipose tissue by MRI. MATERIAL AND METHODS: A total of 20 patients underwent whole-abdomen MRI. A total of 32 transverse T1-weighted images were acquired from each subject. The data collected were transferred to a dedicated workstation and analyzed by both our unsupervised method and a manual procedure. The proposed methodology allows the automatic processing of MRI axial images, segmenting the adipose tissue by fuzzy clustering approach. The use of an active contour algorithm on image masks provided by the fuzzy clustering algorithm allows the separation of subcutaneous fat from visceral fat. Finally, an automated procedure based on automatic image histogram analysis identifies the visceral fat. RESULTS: The accuracy, reproducibility, and speed of our automatic method were compared with the state-of-the-art manual approach. The unsupervised analysis correlated well with the manual analysis, and was significantly faster than manual tracing. Moreover, the unsupervised method was not affected by intraobserver and interobserver variability. CONCLUSION: The results obtained demonstrate that the proposed method can provide the volume of subcutaneous adipose tissue, visceral adipose tissue, global adipose tissue, and the ratio between subcutaneous and visceral fat in an unsupervised and effective manner.

Abdominal Cavity↗
PubMed2006

Comparative study into the robustness of compartmental modeling and model-free analysis in DCE-MRI studies.

PURPOSE: To evaluate and compare the reproducibility of the preferred phenomenological parameter IAUC60 (initial area under the time-concentration curve [IAUC] defined over the first 60 seconds postenhancement) with the preferred modeling parameter (K(trans)), as derived using two simple models, in abdominal and cerebral data collected in typical Phase I clinical trial conditions. MATERIALS AND METHODS: Dynamic contrast enhanced MRI (DCE-MRI) time series were acquired at two imaging centers from a group of patients with abdominal tumors and a group with gliomas. At both imaging centers, precontrast T1 was calculated using a variable flip angle three-dimensional spoiled gradient echo acquisition that was used to quantify tissue contrast agent concentration, allowing voxelwise definition of summary DCE-MRI parameters. RESULTS: A comparison of reproducibility showed that there was no statistically significant difference in reproducibility between IAUC60 and K(trans), although there was a trend towards better reproducibility for K(trans) (P = 0.0782). The 95% confidence intervals (CIs) for individual changes showed that for IAUC60 and K(trans), changes in excess of 47% and 31%, respectively, are outside the range of normal variability. CONCLUSION: Although modeling is more complex and more computationally intensive than an IAUC parameterization, our data suggest this approach to be preferable to a model-free approach since it provides greater physiological insight without a reduction in statistical power for Phase I/II clinical drug trials.

Abdominal Neoplasms↗
PubMed2025

Integrating Enzyme-DNA Complex and CRISPR/Cas12a for Robust Norovirus Detection.

Human norovirus (NoV) is a primary cause of acute gastroenteritis in children, making accurate and rapid detection essential for effective disease prevention and control. In this study, we developed a sensitive and efficient platform for pathogen nucleic acid detection by integrating asymmetric nucleic acid sequence-based amplification (asymmetric NASBA), enzyme-DNA molecular complex, and the clustered regularly interspaced short palindromic repeats (CRISPR) system, namely an A-enDMC platform. The target recognition capability of the enzyme-DNA complex operates independently from the signal amplification function of the CRISPR system. By decoupling the CRISPR reaction from the dependence on specific target sequences, the platform's universality and modularity are enhanced. The assay is fast (<&#x2009;1.5 h), highly sensitive (<&#x2009;5&#x2009;copies/&#xb5;L), and demonstrates no cross-reactivity with other common viruses. Compared to the widely used RT-qPCR method, the platform demonstrates high consistency in detection results, with the detection coincidence rate of 96.77% and a kappa value of 0.87. This platform provides a versatile technological tool for highly sensitive and specific RNA detection, demonstrating its extensive potential in real sample analysis.

Norovirus↗
PubMed2006

Low cost, robust, in-house hardware for heart cutting two-dimensional gas chromatography.

Natural materials are so complex that no single column can separate all of the components. Heart cutting 2-D GC (GC-GC) using a Deans switch provides maximum separation, but the requisite gas flow configurations have earned a reputation for being fiddly and time consuming to set up and tune, unless electronic gas controls and costly software are employed. A design for a vented Deans switch is presented that can be assembled in-house from standard commercial components. A vent to atmosphere replaces the balancing resistor, which solves the problem of balancing the pressures and flows, and requires no compensation for changes in gas viscosity and back-pressure during temperature programming. First and second dimension columns can both be run at optimum flow rates, even if they are of different diameters. Analyte detectability is preserved by cutting only the target fraction from the first column and transferring the whole of it to the second column. Cryotrapping the selected fraction allows cuts of any width, and transfer of analytes to the second column as sharp bands. I have applied the vented Deans switch-cold trap to the identification of flavour and fragrance compounds from South African plants and foods; cuts are very repeatable, and the detectability of trace components is enhanced. Its capabilities are demonstrated by examples from analyses of essential oils and flavour extracts.

Journal Article↗
PubMed2006

Robust and versatile interpretation of spectra with coupled evolution periods using multi-way decomposition.

Coupling of evolution periods in NMR experiments is a very promising approach that has recently attracted much attention for its substantial savings in measurement time. Another novel concept, which has already proved useful in many types of NMR applications is multi-way decomposition. The PRODECOMP tool described here addresses the combination of these two modern tools in protein NMR. The following properties of this approach are described and illustrated. Highly similar information to what would be found in a corresponding full-dimensional spectrum is extracted from a set of projected spectra. All experimental spectra are used simultaneously, avoiding sensitivity loss associated with individual examination of the spectra. Aliasing caused by the linear combinations of individual shifts in the projected spectra is automatically resolved, allowing for better resolution due to smaller spectral widths. Reconstructions of various high-dimensional spectra, including the corresponding full-dimensional spectrum become straightforward. Spectral overlap is efficiently resolved. The capabilities of PRODECOMP are illustrated for a 14 kD protein, for which 12 projections of a 5-dimensional spectrum with the nuclei N, HN, CO, Calpha and Halpha are analysed.

Algorithms↗
PubMed2003

Robust myelin water quantification: averaging vs. spatial filtering.

The myelin water fraction is calculated, voxel-by-voxel, by fitting decay curves from a multi-echo data acquisition. Curve-fitting algorithms require a high signal-to-noise ratio to separate T(2) components in the T(2) distribution. This work compared the effect of averaging, during acquisition, to data postprocessed with a noise reduction filter. Forty regions, from five volunteers, were analyzed. A consistent decrease in the myelin water fraction variability with no bias in the mean was found for all 40 regions. Images of the myelin water fraction of white matter were more contiguous and had fewer "holes" than images of myelin water fractions from unfiltered echoes. Spatial filtering was effective for decreasing the variability in myelin water fraction calculated from 4-average multi-echo data.

Algorithms↗
PubMed1992

Correction of chemical-shift artifacts in 19F imaging of PFOB: a robust signed magnitude method.

This paper describes a method for correcting the chemical-shift artifacts in 19F NMR imaging of perfluoroctylbromide emulsion (PFOB) by utilizing the two spectral peaks of PFOB which have a long T2 value in conjunction with the Dixon method. Corrected images are obtained from the magnitude of the measured images using the sign determined from the phase images. The method was tested in the presence of several phase deformation factors, such as static magnetic field inhomogeneity and inaccurate time shift of the pi refocusing pulse, which affect the phase errors of each pixel in the reconstructed image. The advantage of the signed magnitude method is demonstrated experimentally by comparing it with the currently used complex and magnitude summation/subtraction methods.

Artifacts↗
PubMed1992

Twisting radial lines with application to robust magnetic resonance imaging of irregular flow.

A problem with magnetic resonance angiograms of vessels containing irregular flow is that flow-induced dephasing can result in voids in the image. These void regions are susceptible to misinterpretation as regions of stenosis or other vessel pathology. Flow-induced dephasing can be minimized by using radial lines to cover k space. However, radial lines provide a very nonuniform, and hence, inefficient, coverage of k space. By twisting the outer portions of the radial trajectories, undistorted images of very rapid and turbulent flow can be obtained with a reasonable number of RF excitations.

Blood Flow Velocity↗