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At least 1,027 records · Page 57Linked to original sources
PubMed2004

An accurate, robust, and computationally efficient navigator algorithm for measuring diaphragm positions.

PURPOSE: The purpose of this study is to develop an improved algorithm for measuring the position of the diaphragm using navigator echoes. METHODS: This algorithm was applied to navigator echo data acquired from 14 cardiac patients. For each patient, 160 navigator echo profiles were acquired across the right hemi-diaphragm along the superior-inferior direction. RESULTS: The accuracy of the proposed edge-detection algorithm was evaluated together with that of the least-squares and linear phase-shift algorithms. The estimated measurement error of the proposed algorithm was approximately two times smaller than that of the least-squares algorithm (Magn Reson Med, 1996:36: 117-123), and was approximately four times smaller than that of the linear phase-shift algorithm (Magn Reson Med, 1999;42:548-553). The computational efficiency of this algorithm was 7.5 times higher than that of the least-squares algorithm and was comparable with that of the linear phase-shift algorithm. CONCLUSION: The presented algorithm is accurate, robust, and computationally efficient in the measurement of the diaphragm position.

Adult↗
PubMed2004

Robust cell polarity is a dynamic state established by coupling transport and GTPase signaling.

Yeast cells can initiate bud formation at the G1/S transition in a cue-independent manner. Here, we investigate the dynamic nature of the polar cap and the regulation of the GTPase Cdc42 in the establishment of cell polarity. Using analysis of fluorescence recovery after photobleaching, we found that Cdc42 exchanged rapidly between the polar caps and cytosol and that this rapid exchange required its GTPase cycle. A previously proposed positive feedback loop involving actomyosin-based transport of the Cdc42 GTPase is required for the generation of robust cell polarity during bud formation in yeast. Inhibition of actin-based transport resulted in unstable Cdc42 polar caps. Unstable polarity was also observed in mutants lacking Bem1, a protein previously implicated in a feedback loop for Cdc42 activation through a signaling pathway. When Bem1 and actin were both inhibited, polarization completely failed. These results suggest that cell polarity is established through coupling of transport and signaling pathways and maintained actively by balance of flux.

Actins↗
PubMed1998

Robustness and power of the maximum-likelihood-binomial and maximum-likelihood-score methods, in multipoint linkage analysis of affected-sibship data.

The maximum-likelihood-binomial (MLB) method, based on the binomial distribution of parental marker alleles among affected offspring, recently was shown to provide promising results by two-point linkage analysis of affected-sibship data. In this article, we extend the MLB method to multipoint linkage analysis, using the general framework of hidden Markov models. Furthermore, we perform a large simulation study to investigate the robustness and power of the MLB method, compared with those of the maximum-likelihood-score (MLS) method as implemented in MAPMAKER/SIBS, in the multipoint analysis of different affected-sibship samples. Analyses of multiple-affected sibships by means of the MLS were conducted by consideration of all possible sib pairs, with (weighted MLS [MLSw]) or without (unweighted MLS [MLSu]) application of a classic weighting procedure. In simulations under the null hypothesis, the MLB provided very consistent type I errors regardless of the type of family sample (sib pairs or multiple-affected sibships), as did the MLS for samples with sib pairs only. When samples included multiple-affected sibships, the MLSu led to inflation of low type I errors, whereas the MLSw yielded very conservative tests. Power comparisons showed that the MLB generally was more powerful than the MLS, except in recessive models with allele frequencies <.3. Missing parental marker data did not strongly influence type I error and power results in these multipoint analyses. The MLB approach, which in a natural way accounts for multiple-affected sibships and which provides a simple likelihood-ratio test for linkage, is an interesting alternative for multipoint analysis of sibships.

Computer Simulation↗
PubMed1999

Testing the robustness of the likelihood-ratio test in a variance-component quantitative-trait loci-mapping procedure.

Detection of linkage to genes for quantitative traits remains a challenging task. Recently, variance components (VC) techniques have emerged as among the more powerful of available methods. As often implemented, such techniques require assumptions about the phenotypic distribution. Usually, multivariate normality is assumed. However, several factors may lead to markedly nonnormal phenotypic data, including (a) the presence of a major gene (not necessarily linked to the markers under study), (b) some types of gene x environment interaction, (c) use of a dichotomous phenotype (i.e., affected vs. unaffected), (d) nonnormality of the population within-genotype (residual) distribution, and (e) selective (extreme) sampling. Using simulation, we have investigated, for sib-pair studies, the robustness of the likelihood-ratio test for a VC quantitative-trait locus-detection procedure to violations of normality that are due to these factors. Results showed (a) that some types of nonnormality, such as leptokurtosis, produced type I error rates in excess of the nominal, or alpha, levels whereas others did not; and (b) that the degree of type I error-rate inflation appears to be directly related to the residual sibling correlation. Potential solutions to this problem are discussed. Investigators contemplating use of this VC procedure are encouraged to provide evidence that their trait data are normally distributed, to employ a procedure that allows for nonnormal data, or to consider implementation of permutation tests.

Analysis of Variance↗
PubMed2000

Testing the robustness of the new Haseman-Elston quantitative-trait loci-mapping procedure.

Variance components (VC) techniques have emerged as among the more powerful methods for detection of quantitative-trait loci (QTL) in linkage analysis. Allison et al. found that, with particularly marked leptokurtosis in the phenotypic distribution and moderate-to-high residual sibling correlation, maximum likelihood (ML) VC methods may produce a severe excess of type I errors. The new Haseman-Elston (NHE) method is a least-squares-based VC method for mapping of QTL in sib pairs (Elston et al.). Using simulation, we investigate the robustness of the NHE to marked nonnormality, by means of the same distributions and worst-case conditions identified by Allison et al. for the ML approach (i.e., 100 pairs; high residual sibling correlation). Results showed that, when marked nonnormality is present, the NHE can be used without severe type I error-rate inflation, even at very small alpha levels.

Chromosome Mapping↗
PubMed2004

A powerful and robust new linkage statistic for discordant sibling pairs.

Previously, Szatkiewicz and colleagues evaluated the performance of a wide variety of statistics for quantitative-trait-locus linkage, using discordant sibling pairs. They found that the most powerful statistics, in general, were a score statistic and a "composite statistic." However, whereas these two statistics have equal power under ideal conditions, each has limitations that reduce its power in certain circumstances. The score statistic depends on estimates of trait parameters and can lose a lot of power if those estimates are incorrect. The composite statistic is not sensitive to trait-parameter estimates but does depend on arbitrary weights that must be chosen on the basis of the ascertainment scheme. In this report, we elucidate the algebraic relationship between the score and composite statistics and then use that relationship to suggest a new statistic that combines the best properties of both. We call our new statistic the "robust discordant pair" (RDP) statistic. We report simulation studies to show that the RDP statistic does, indeed, have all of the strengths and none of the weaknesses of the score and composite statistics.

Computer Simulation↗
PubMed2004

The consequences for human reproduction of a robust inflammatory response.

Innate and adaptive immune responsiveness is variable within the population. Since robust immune reactions are critical to the survival of humans, the existence of immune variability in the population suggests the existence of competing, alternative phenotypes. Although women with powerful immune responsiveness may be more likely to survive to reproduce, their reproductive experiences may be less successful than women who are not as responsive. Normal pregnancy elicits a maternal inflammatory reaction. This can be understood on the basis of maternal-fetal conflict theory: inflammation is a component of the maternal attempt to limit excessive fetal demands. However, an overly aggressive inflammatory reaction has been shown to relate to a variety of adverse reproductive outcomes. Reviewed here are several examples, including the fallopian tube damage that results from pelvic inflammatory disease, the upregulated inflammatory response among women who develop preeclampsia, an association between immune hyperresponsiveness and premature delivery, and the relationship between autoimmune diseases and multiple adverse pregnancy outcomes. The hypothesis that immune hyperresponsiveness limits reproductive capacity suggests many avenues for research.

Autoimmunity↗
PubMed2005

Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.

Abnormalities, Multiple↗
PubMed2005

Robust genomic control for association studies.

Population-based case-control studies are a useful method to test for a genetic association between a trait and a marker. However, the analysis of the resulting data can be affected by population stratification or cryptic relatedness, which may inflate the variance of the usual statistics, resulting in a higher-than-nominal rate of false-positive results. One approach to preserving the nominal type I error is to apply genomic control, which adjusts the variance of the Cochran-Armitage trend test by calculating the statistic on data from null loci. This enables one to estimate any additional variance in the null distribution of statistics. When the underlying genetic model (e.g., recessive, additive, or dominant) is known, genomic control can be applied to the corresponding optimal trend tests. In practice, however, the mode of inheritance is unknown. The genotype-based chi (2) test for a general association between the trait and the marker does not depend on the underlying genetic model. Since this general association test has 2 degrees of freedom (df), the existing formulas for estimating the variance factor by use of genomic control are not directly applicable. By expressing the general association test in terms of two Cochran-Armitage trend tests, one can apply genomic control to each of the two trend tests separately, thereby adjusting the chi (2) statistic. The properties of this robust genomic control test with 2 df are examined by simulation. This genomic control-adjusted 2-df test has control of type I error and achieves reasonable power, relative to the optimal tests for each model.

Case-Control Studies↗
PubMed1994

A robust method of multileaf collimator (MLC) leaf-configuration verification.

Presents a novel and robust method for leaf-position verification with a multileaf collimator (MLC). On the portal image associated with an MLC-generated treatment field, all true treatment-held-edge lines are either parallel or perpendicular to each other. This unique feature of an MLC treatment field has been fully exploited by the authors' method. Employing a Hough-type transformation as an edge-line-orientation detector and a chamfer-matching method, the authors can find the best matching parameters (including translation, rotation and scaling) adaptively between a prescribed MLC leaf configuration and the actual treatment-held edges generated by the MLC system. This works even if the portal image is partially corrupted by noise or covered by compact bony structures. Comparing these parameters with clinically accepted tolerances, the authors can make a "go-or-no-go" decision quickly.

Algorithms↗
PubMed1997

A theoretical study of the robustness of the isovolume calibration method for a two-compartment model of breathing, based on an analysis of the connected cylinders model.

The use of the isovolume manoeuvre method as a calibration technique for respiratory monitoring instrumentation that detects the movement of the ribcage and the abdominal wall is analysed based on a model of two connected cylinders whose radii and heights may vary, and evidence is presented which suggests that this calibration method is robust in most circumstances. Some possible functional forms relating the variations in cylinder radius and height are examined, and methods for obtaining calibration constants based on these functional forms, purely from measurements of variations in the cylinder radius, are presented.

Humans↗
PubMed2005

Robust optimization for intensity modulated radiation therapy treatment planning under uncertainty.

The recent development of intensity modulated radiation therapy (IMRT) allows the dose distribution to be tailored to match the tumour's shape and position, avoiding damage to healthy tissue to a greater extent than previously possible. Traditional treatment plans assume that the target structure remains in a fixed location throughout treatment. However, many studies have shown that because of organ motion, inconsistencies in patient positioning over the weeks of treatment, etc, the tumour location is not stationary. We present a probabilistic model for the IMRT inverse problem and show that it is identical to using robust optimization techniques, under certain assumptions. For a sample prostate case, our computational results show that this method is computationally feasible and promising-compared to traditional methods, our model has the potential to find treatment plans that are more adept at sparing healthy tissue while maintaining the prescribed dose to the target.

Algorithms↗
PubMed2006

Efficient schemes for robust IMRT treatment planning.

We use robust optimization techniques to formulate an IMRT treatment planning problem in which the dose matrices are uncertain, due to both dose calculation errors and interfraction positional uncertainty of tumour and organs. When the uncertainty is taken into account, the original linear programming formulation becomes a second-order cone program. We describe a novel and efficient approach for solving this problem, and present results to compare the performance of our scheme with more conventional formulations that assume perfect knowledge of the dose matrix.

Algorithms↗
PubMed2001

Robust HIV type 2 cellular immune response measured by a modified anthrax toxin-based enzyme-linked immunospot assay.

Evaluation of immune mechanisms responsible for control of viral replication is critical to understanding HIV-2 attenuated biological characteristics in pathogenesis and transmission. Evaluation of the cellular immune response is often based on labor-intensive techniques that limit the scope of most studies performed. A simple and rapid anthrax toxin-based ELISPOT method to assess HIV-2 cellular immune response was developed. The modified anthrax toxin-based antigen presentation process performed better than a recombinant vaccinia system and the ELISPOT method significantly enhanced the ease and simplicity of the assay. Using this method, a robust HIV-2 cellular immune response directed toward the p26 core protein was exhibited in 21 of 24 (87.5%) infected women, and all 8 seronegative subjects were negative in both assays. Cellular immune responses were associated with low HIV-2 viral load. This simple and rapid modified anthrax toxin-based ELISPOT method allowed us to demonstrate, strong cellular immune responses that may be critical determinants in the HIV-2 attenuated phenotype.

Antigen Presentation↗
PubMed2001

Robust prostate-specific expression for targeted gene therapy based on the human kallikrein 2 promoter.

Tissue-specific transcriptional regulatory elements can increase the safety of gene therapy vectors. Unlike prostate-specific antigen (PSA/hK3), whose expression displays an inverse correlation with prostate cancer grade and stage, human glandular kallikrein 2 (hK2) is upregulated in higher grade and stage disease. Therefore, our goal was to develop a strong and prostate-specific hK2-based promoter for targeted gene therapy. We identified the minimum "full-strength" hK2 enhancer and built transcriptional regulatory elements composed of multiple tandem copies of this 1.2-kb enhancer, fused to the hK2 minimal promoter. Relative to the weak induction of the minimal hK2 promoter by androgen analog (R1881) in androgen receptor (AR)-positive LNCaP cells, transcriptional activity was increased by 25-, 44-, 81-, and 114-fold when one to four enhancers were spliced to the hK2 promoter, respectively. In contrast, the enhancer/promoter elements were inactive in the AR(-) prostate cancer line PC-3 and in a panel of nonprostate lines, including 293, U87, MCF-7, HuH-7, and HeLa cells. Furthermore, we generated a recombinant adenovirus, ADV.hK2-E3/P-EGFP, expressing enhanced green fluorescent protein (EGFP) under the control of the hK2 triplicate enhancer/promoter, and compared its properties with ADV.CMV-EGFP expressing EGFP under the control of the cytomegalovirus (CMV) enhancer/promoter. Unlike the CMV promoter, the hK2-E3/P promoter was at least 100-fold inducible by R1881 in the adenoviral backbone. Compared with in situ injection of subcutaneous LNCaP tumors with ADV.CMV-EGFP, which led to detectable EGFP expression in tumor, liver, and brain tissue, ADV.hK2-E3/P-EGFP injection led to robust but tumor-restricted EGFP expression. These results suggest that the hk2 multienhancer/promoter should be a powerful novel reagent for safer targeted gene therapy of prostate cancer.

Adenoviridae↗
PubMed2003

Robustness of inference of haplotype block structure.

In this report, we examine the validity of the haplotype block concept by comparing block decompositions derived from public data sets by variants of several leading methods of block detection. We first develop a statistical method for assessing the concordance of two block decompositions. We then assess the robustness of inferred haplotype blocks to the specific detection method chosen, to arbitrary choices made in the block-detection algorithms, and to the sample analyzed. Although the block decompositions show levels of concordance that are very unlikely by chance, the absolute magnitude of the concordance may be low enough to limit the utility of the inference. For purposes of SNP selection, it seems likely that methods that do not arbitrarily impose block boundaries among correlated SNPs might perform better than block-based methods.

Algorithms↗
PubMed2002

Rapid and robust screening of the Menkes disease/occipital horn syndrome gene.

Menkes disease and occipital horn syndrome (OHS) are allelic neurogenetic disorders of copper transport associated with mutations in an X-linked gene, ATP7A. This gene encodes a copper-transporting P-type ATPase. The spectrum of mutations at the Menkes/OHS locus is estimated to include 1% chromosomal rearrangements and 15-20% large deletions, with the remaining defects involving small alterations. There is a compelling need for a rapid and reliable molecular diagnostic approach for patients and families impacted by these conditions. In addition to testing suspected affected males, carrier screening of females in Menkes/OHS families and prenatal evaluation of at-risk pregnancies will be enhanced by the wider availability of robust mutation analysis for this large (23-exon) locus. Here we describe a stepwise approach to mutation screening for these disorders that successfully identified molecular alterations in over 95% of our patient population (n = 49). This genomic DNA-based technique employs multiplex PCR, heteroduplex analysis, and direct sequencing, in a serial fashion. This approach should find application in molecular diagnostic laboratories in the United States and other countries. Currently, only a single European center provides commercial testing for unknown mutations in Menkes/OHS patients, even though these disorders occur worldwide.

Adenosine Triphosphatases↗
PubMed2003

Robust levels of long-term multilineage reconstitution in the absence of stem cell self-replication in W/Wv mice transplanted with purified stem cells.

Isolation of primitive blood stem cells by different methods results in cell populations with distinct biological activities. This study was aimed at resolving differences in the frequency of multilineage reconstituting cells (MRC) and their precursors (pMRC) in cell populations isolated by positive selection for Sca-1 compared to those isolated by negative selection for 15-1.1. Separation of wheat germ agglutinin-positive mouse bone marrow cells into 15-1.1neg or Sca-1+ subsets was performed by flow cytometry. The isolated cells were transplanted into W/Wv or normal irradiated recipient mice and reconstitution was evaluated over time. Sca-1+ cells were less frequent and contained more MRC than 15-1.1neg cells, while pMRC were found mainly among 15-1.1neg cells. MRC activity was exclusively contained within the Sca-1+ subpopulation of 15-1.1neg cells, but marrow from 7 robustly engrafted W/Wv mice did not contain donor-derived MRC, indicating that 15-1.1negSca-1+ cells contain low numbers of pMRC. Functional differences between 15-1.1neg and Sca-1+ cells were further confirmed by reverse transcriptase (RT)-PCR gene expression analysis. Early hematopoiesis-specific transcription factors (Scl, Gata-2, and Gata-1) were amplified from cDNA prepared from Sca-1+ but not 15-1.1neg cells. This study indicates that cell populations isolated as Sca-1+ are functionally distinct from those isolated as 15-1.1neg in that few pMRC are included among Sca-1+ cells and that MRC and pMRC are two distinct and separable cell populations.

Animals↗