bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of a unified analysis approach for family and unrelated samples with the transmission-disequilibrium test to study associations of hypertension in the Framingham Heart Study
Authors: Sun Xiangqing , Feng Tao , Song Yeunjoo , Elston Robert C , Zhu Xiaofeng
Published: December 2009

Population stratification is one of the major causes of spurious associations in association studies. A unified association approach based on principal-component analysis can overcome the effect of population stratification, as well as make use of both family and unrelated samples combined to increase power (family-case-control, or FamCC). In this study, we compared FamCC and the transmission-disequilibrium test (TDT) using data on hypertension, systolic blood pressure, and diastolic blood pressure in the Framingham Heart Study. Our study indicated FamCC has reasonable type I error for both the unrelated sample and the family sample for all three traits. For these three traits, we found results from FamCC were inconsistent with those from the TDT. We discuss the reasons for this inconsistency. After correcting for multiple tests, we did not detect any significant single-nucleotide polymorphisms by either FamCC or the TDT.
Application of seventeen two-locus models in genome-wide association studies by two-stage strategy
Authors: Niu Adan , Zhang Zhaogong , Sha Qiuying
Published: December 2009

The goal of this paper is to search for two-locus combinations that are jointly associated with rheumatoid arthritis using the data set of Genetic Analysis Workshop 16 Problem 1. We use a two-stage strategy to reduce the computational burden associated with performing an exhaustive two-locus search across the genome. In the first stage, the full set of 531,689 single-nucleotide polymorphisms was screened using univariate testing. In the second stage, all pairs made from the 500 single-nucleotide polymorphisms with the lowest p-values from the first stage were evaluated under each of 17 two-locus models. Our analyses identified a two-locus combination - rs6939589 and rs11634386 - that proved to be significantly associated with rheumatoid arthritis under a Rec × Rec model (p-value = 0.045 after adjusting for multiple tests and multiple models).
Multivariate association analysis of the components of metabolic syndrome from the Framingham Heart Study
Authors: Baker Allison R , Goodloe Robert J , Larkin Emma K , Baechle Dan J , Song Yeunjoo E , Phillips Lynette S , Gray-McGuire Courtney L
Published: December 2009

Metabolic syndrome, by definition, is the manifestation of multiple, correlated metabolic impairments. It is known to have both strong environmental and genetic contributions. However, isolating genetic variants predisposing to such a complex trait has limitations. Using pedigree data, when available, may well lead to increased ability to detect variants associated with such complex traits. The ability to incorporate multiple correlated traits into a joint analysis may also allow increased detection of associated genes. Therefore, to demonstrate the utility of both univariate and multivariate family-based association analysis and to identify possible genetic variants associated with metabolic syndrome, we performed a scan of the Affymetrix 50 k Human Gene Panel data using 1) each of the traits comprising metabolic syndrome: triglycerides, high-density lipoprotein, systolic blood pressure, diastolic blood pressure, blood glucose, and body mass index, and 2) a composite trait including all of the above, jointly. Two single-nucleotide polymorphisms within the cholesterol ester transfer protein (CETP) gene remained significant even after correcting for multiple testing in both the univariate (p < 5 × 10-7) and multivariate (p < 5 × 10-9) association analysis. Three genes met significance for multiple traits after correction for multiple testing in the univariate analysis, while five genes remained significant in the multivariate association. We conclude that while both univariate and multivariate family-based association analysis can identify genes of interest, our multivariate approach is less affected by multiple testing correction and yields more significant results.
Predictive modeling in case-control single-nucleotide polymorphism studies in the presence of population stratification: a case study using Genetic Analysis Workshop 16 Problem 1 dataset
Authors: Arshadi Niloofar , Chang Billy , Kustra Rafal
Published: December 2009

In this paper, we apply the gradient-boosting machine predictive model to the rheumatoid arthritis data for predicting the case-control status. QQ-plot suggests severe population stratification. In univariate genome-wide association studies, a correction factor for ethnicity confounding can be derived. Here we propose a novel strategy to deal with population stratification in the context of multivariate predictive modeling. We address the problem by clustering the subjects on the axes of genetic variations, and building a predictive model separately in each cluster. This allows us to control ethnicity without explicitly including it in the model, which could marginalize the genetic signal we are trying to discover. Clustering not only leads to more similar ethnicity groups but also, as our results show, increases the accuracy of our model when compared to the non-clustered approach. The highest accuracy is achieved with the model adjusted for population stratification, when the genetic axes of variation are included among the set of predictors, although this may be misleading given the confounding effects.
Detecting single-nucleotide polymorphism by single-nucleotide polymorphism interactions in rheumatoid arthritis using a two-step approach with machine learning and a Bayesian threshold least absolute shrinkage and selection operator (LASSO) model
Authors: González-Recio Oscar , de Maturana Evangelina López , Vega Andrés T , Engelman Corinne D , Broman Karl W
Published: December 2009

The objective of this study was to detect interactions between relevant single-nucleotide polymorphisms (SNPs) associated with rheumatoid arthritis (RA). Data from Problem 1 of the Genetic Analysis Workshop 16 were used. These data consisted of 868 cases and 1,194 controls genotyped with the 500 k Illumina chip. First, machine learning methods were applied for preselecting SNPs. One hundred SNPs outside the HLA region and 1,500 SNPs in the HLA region were preselected using information-gain theory. The softwarewekawas used to reduce colinearity and redundancy in the HLA region, resulting in a subset of 6 SNPs out of 1,500. In a second step, a parametric approach to account for interactions between SNPs in the HLA region, as well as HLA-nonHLA interactions was conducted using a Bayesian threshold least absolute shrinkage and selection operator (LASSO) model incorporating 2,560 covariates. This approach detected some main and interaction effects for SNPs in genes that have previously been associated with RA (e.g., rs2395175, rs660895, rs10484560, and rs2476601). Further, some other SNPs detected in this study may be considered in candidate gene studies.
Identification of genes and haplotypes that predict rheumatoid arthritis using random forests
Authors: Tang Rui , Sinnwell Jason P , Li Jia , Rider David N , de Andrade Mariza , Biernacka Joanna M
Published: December 2009

Random forest (RF) analysis of genetic data does not require specification of the mode of inheritance, and provides measures of variable importance that incorporate interaction effects. In this paper we describe RF-based approaches for assessment of gene and haplotype importance, and apply these approaches to a subset of the North American Rheumatoid Arthritis Consortium case-control data provided by Genetic Analysis Workshop 16. The RF analyses of 37 genes identified many of the same genes as logistic regression, but also suggested importance of certain single-nucleotide polymorphism and genes that were not ranked highly by logistic regression. A new permutation method did not reveal strong evidence of gene-gene interaction effects in these data. Although RFs are a promising approach for genetic data analysis, extensions beyond simple single-nucleotide polymorphism analyses and modifications to improve computational feasibility are needed.
Detecting significant single-nucleotide polymorphisms in a rheumatoid arthritis study using random forests
Authors: Wang Minghui , Chen Xiang , Zhang Meizhuo , Zhu Wensheng , Cho Kelly , Zhang Heping
Published: December 2009

Random forest is an efficient approach for investigating not only the effects of individual markers on a trait but also the effect of the interactions among the markers in genetic association studies. This approach is especially appealing for the analysis of genome-wide data, such as those obtained from gene expression/single-nucleotide polymorphism (SNP) array experiments in which the number of candidate genes/SNPs is vast. We applied this approach to the Genetic Analysis Workshop 16 Problem 1 data to identify SNPs that contribute to rheumatoid arthritis. The random forest computed a raw importance score for each SNP marker, where higher importance score suggests higher level of association between the marker and the trait. The significance level of the association was determined empirically by repeatedly reapplying the random forest on randomly generated data under the null hypothesis that no association exists between the markers and the trait. Using random forest, we were able to identify 228 significant SNPs (at the genome-wide significant level of 0.05) across the whole genome, over two-thirds of which are located on chromosome 6, especially clustered in the region of 6p21 containing the human leukocyte antigen (HLA) genes, such as gene HLA-DRB1 and HLA-DRA. Further analysis of this region indicates a strong association to the rheumatoid arthritis status.
Classification tree for detection of single-nucleotide polymorphism (SNP)-by-SNP interactions related to heart disease: Framingham Heart Study
Authors: Yao Li , Zhong Wenjun , Zhang Zhumin , Maenner Matthew J , Engelman Corinne D
Published: December 2009

The aim of this study was to detect the effect of interactions between single-nucleotide polymorphisms (SNPs) on incidence of heart diseases. For this purpose, 2912 subjects with 350,160 SNPs from the Framingham Heart Study (FHS) were analyzed. PLINK was used to control quality and to select the 10,000 most significant SNPs. A classification tree algorithm, Generalized, Unbiased, Interaction Detection and Estimation (GUIDE), was employed to build a classification tree to detect SNP-by-SNP interactions for the selected 10 k SNPs. The classes generated by GUIDE were reexamined by a generalized estimating equations (GEE) model with the empirical variance after accounting for potential familial correlation. Overall, 17 classes were generated based on the splitting criteria in GUIDE. The prevalence of coronary heart disease (CHD) in class 16 (determined by SNPs rs1894035, rs7955732, rs2212596, and rs1417507) was the lowest (0.23%). Compared to class 16, all other classes except for class 288 (prevalence of 1.2%) had a significantly greater risk when analyzed using GEE model. This suggests the interactions of SNPs on these node paths are significant.
Comparative analysis of different approaches for dealing with candidate regions in the context of a genome-wide association study
Authors: Lantieri Francesca , Jhun Min A , Park Jungsun , Park Taesung , Devoto Marcella
Published: December 2009

Genome-wide association studies (GWAS) test hundreds of thousands of single-nucleotide polymorphisms (SNPs) for association to a trait, treating each marker equally and ignoring prior evidence of association to specific regions. Typically, promising regions are selected for further investigation based onp-values obtained from simple tests of association. However, loci that exert only a weak, low-penetrant role on the trait, producing modest evidence of association, are not detectable in the context of a GWAS. Implementing prior knowledge of association in GWAS could increase power, help distinguish between false and true positives, and identify better sets of SNPs for follow-up studies.

Here we performed a GWAS on rheumatoid arthritis (RA) patients and controls (Problem 1, Genetic Analysis Workshop 16). In order to include prior information in the analysis, we applied four methods that distinctively deal with markers in candidate genes in the context of GWAS. SNPs were divided into a random and a candidate subset, then we applied empirical correction by permutation, false-discovery rate, false-positive report probability, and posterior odds of association using different prior probabilities. We repeated the same analyses on two different sets of candidate markers defined on the basis of previously reported association to RA following two different approaches. The four methods showed similar relative behavior when applied to the two sets, with the proportion of candidate SNPs ranked among the top 2,000 varying from 0 to 100%. The use of different prior probabilities changed the stringency of the methods, but not their relative performance.
Comparison of univariate and multivariate linkage analysis of traits related to hypertension
Authors: Gray-McGuire Courtney , Song Yeunjoo , Morris Nathan J , Stein Catherine M
Published: December 2009

Complex traits are often manifested by multiple correlated traits. One example of this is hypertension (HTN), which is measured on a continuous scale by systolic blood pressure (SBP). Predisposition to HTN is predicted by hyperlipidemia, characterized by elevated triglycerides (TG), low-density lipids (LDL), and high-density lipids (HDL). We hypothesized that the multivariate analysis of TG, LDL, and HDL would be more powerful for detecting HTN genes via linkage analysis compared with univariate analysis of SBP. We conducted linkage analysis of four chromosomal regions known to contain genes associated with HTN using SBP as a measure of HTN in univariate Haseman-Elston regression and using the correlated traits TG, LDL, and HDL in multivariate Haseman-Elston regression. All analyses were conducted using the Framingham Heart Study data. We found that multivariate linkage analysis was better able to detect chromosomal regions in which the angiotensinogen, angiotensin receptor, guanine nucleotide-binding protein 3, and prostaglandin I2 synthase genes reside. Univariate linkage analysis only detected the AGT gene. We conclude that multivariate analysis is appropriate for the analysis of multiple correlated phenotypes, and our findings suggest that it may yield new linkage signals undetected by univariate analysis.
In vivo confocal microscopy of an apparent deep stroma corneal dystrophy: a case report
Authors: Lanza Michele , Borrelli Maria , Benusiglio Enrico , Rosa Nicola
Published: December 2009

A 41-year-old white woman was referred to our Department to rule out the presence of a Fuch's corneal dystrophy. On slit-lamp biomicroscopy, small bilateral punctuate opacities appearing mostly in the posterior stroma were observed, suggesting a differential diagnosis of pre-Descemet's dystrophy as opposed to Cornea Farinata.

Confocal microscopy in the central cornea of both eyes revealed the normal appearance of superficial and basal epithelial layers. However throughout the full thickness of the cornea fine highly refractive granules, localized both in the keratocytes cytoplasm and in the stroma matrix were noted. In both eyes abnormal polymegatism and pleomorphism was observed.
An unusual complication of Mitek suture anchor use in primary treatment of flexor digitorum profundus tendon laceration: a case report
Authors: Giannikas Dimitrios , Athanaselis Efstratios , Matzaroglou Charalambos , Saridis Alkis , Tyllianakis Minos
Published: December 2009

Introduction

A case of an osteolysis by Mitek anchor-suture is presented.

Case presentation

A case of index finger's flexor digitorum profundus tendon primary reconstruction with the use of Mitek anchor is presented here. Within a 14 month period, Mitek suture anchor caused local foreign body reaction with osteolysis and ulceration of the palmar skin of the finger while on the other hand tendon's healing was successfully completed.

Conclusion

Mitek anchor-sutures can cause an aseptic inflammatory reaction which represents a typical biologic response to a foreign body. Concomitant osteolysis can drive to loosening and migration of the implant.
Penicillin-binding Proteins (PBP) and Lmo0441 (a PBP-like protein) play a role in Beta-lactam sensitivity of Listeria monocytogenes
Authors: Van de Velde Sébastien , Carryn Stéphane , Van Bambeke Françoise , Hill Colin , Tulkens Paul M , Sleator Roy D
Published: December 2009

While seven penicillin-binding proteins (PBPs) or PBP-like proteins have been identified either by radiolabelled penicillin binding studies or genomic analysis, only PBP3 has been considered of interest for Beta-lactams activity againstListeria monocytogenes. Herein we reveal that both PBP4 and Lmo0441 (a PBP-like protein) play a direct role in cephalosporin activity inL. monocytogeneswhile PBP4 additionally has a protective affect against both penicillin and carbapenem.
Global end-diastolic volume acquired by transpulmonary thermodilution depends on age and gender in awake and spontaneously breathing patients
Authors: Wolf Stefan , Rieß Alexander , Landscheidt Julia F , Lumenta Christianto B , Friederich Patrick , Schürer Ludwig
Published: December 2009

Introduction

Volumetric parameters acquired by transpulmonary thermodilution had been repeatedly proven superior to filling pressures for estimation of cardiac preload. Up to now, the proposed normal ranges were never studied in detail. We investigated the relationship of the global end-diastolic volume (GEDV) acquired by transpulmonary thermodilution with age and gender in awake and spontaneously breathing patients.

Methods

Patients requiring brain tumor surgery were equipped prospectively with a transpulmonary thermodilution device. On postoperative day one, thermodilution measurements were performed in 101 patients ready for discharge from the ICU. All subjects were awake, spontaneously breathing, hemodynamically stable and free of catecholamines.

Results

Main finding was a dependence of GEDV on age and gender, height and weight of the patient. Age was a highly significant non-linear coefficient for GEDV with large inter-individual variance (p < 0.001). On average, GEDV was 131.1 ml higher in males (p = 0.027). Each cm body height accounted for 13.0 ml additional GEDV (p < 0.001). GEDV increased by 2.90 ml per kg actual body weight (p = 0.043). Each cofactor, including height and weight, remained significant after indexing GEDV to body surface area using predicted body weight.

Conclusions

The volumetric parameter GEDV shows a large inter-individual variance and is dependent on age and gender. These dependencies persist after indexing GEDV to body surface area calculated with predicted body weight. Targeting resuscitation using fixed ranges of preload volumes acquired by transpulmonary thermodilution without concern to an individual patient's age and gender seems not to be appropriate.
Full-wave-equation depth extrapolation for migration
Authors: Sandberg Kristian , Beylkin Gregory
Published: December 2009

Most of the traditional approaches to migration by downward extrapolation suffer from inaccuracies caused by using one-way propagation, both in the construction of such propagators in a variable background and the suppression of propagating waves generated by, e.g., steep reflectors. We present a new mathematical formulation and an algorithm for downward extrapolation that suppress only the evanescent waves. We show that evanescent wave modes are associated with the positive eigenvalues of the spatial operator and introduce spectral projectors to remove these modes, leaving all propagating modes corresponding to nonpositive eigenvalues intact. This approach suppresses evanescent modes in an arbitrary laterally varying background. If the background velocity is only depth dependent, then the spectral projector may be applied by using the fast Fourier transform and a filter in the Fourier domain. In computing spectral projectors, we use an iteration that avoids the explicit construction of the eigensystem. Moreover, we use a representation of matrices leading to fast matrix-matrix multiplication and, as a result, a fast algorithm necessary for practical implementation of spectral projectors. The overall structure of the migration algorithm is similar to survey sinking with an important distinction of using a new method for downward continuation. Using a blurred version of the true velocity as a background, steep reflectors can be imaged in a 2D slice of the SEG-EAGE model.
Inferring earth structure from combined measurements of rotational and translational ground motions
Authors: Bernauer Moritz , Fichtner Andreas , Igel Heiner
Published: December 2009

We introduce a novel variant of seismic tomography that is based on colocated measurements of rotational and translational ground motions. Our aim is to assess whether rotations may be incorporated successfully into seismic inverse problems to produce better resolved and more realistic tomographic images. Our methodology is based on the definition of apparent S-wave speed as the ratio of rms velocity and rotation amplitudes. The principal advantages of this definition are that (1) no traveltimes measurements are needed and (2) the apparent S-wave speed is independent of source magnitude and source timing. We derive finite-frequency kernels for apparent S-wave speed by using a combination of the adjoint method and ray approximation. The properties of these kernels as a function of frequency bandwidth can be illustrated along with their usefulness for seismic tomography. In multifrequency synthetic inversions, we consider local crosshole tomography and regional-scale earthquake tomography. Our results indicate that S-wave speed variations can be retrieved accurately from colocated rotation and translation measurements, suggesting that our methodology is a promising extension of conventional seismic tomography. Further, apparent S-wave speed can be used to increase vertical resolution in teleseismic tomography for local structures.
Fresnel volume migration of single-component seismic data
Authors: Buske Stefan , Gutjahr Stine , Sick Christof
Published: December 2009

Standard implementations of Kirchhoff prestack depth migration (PSDM) distribute the recorded wavefield along two-way-traveltime isochrons and an image is generated by constructive interference of these isochrons along the actual reflector elements. Beside the recent developments of wave-equation-based approaches, Kirchhoff PSDM is still considered widely as a state-of-the-art technique in obtaining high-quality images of the subsurface, particularly for highly irregular survey layouts and target-oriented imaging tasks. However, for sparse sampling or limited aperture, the resulting image is affected by significant migration noise as a result of limited constructive interference of the back-propagated wavefield. Some modifications have been proposed to reduce these artifacts. These modifications include constructing a specular path of wave propagation, derived from estimates of the emergent angle of coherent phases in the seismogram section, and the mainly heuristic restriction of the imaging operator to the neighborhood of that wavepath. Our approach uses Fresnel volumes to restrict the migration operator in a physically frequency-dependent way. Using the emergent angle at the receiver, determined by a local slowness analysis, a ray is propagated into the subsurface; the back-propagation of the wavefield is restricted to the vicinity of this ray according to its approximated Fresnel volume. This so-called Fresnel volume migration approach enhances image quality significantly compared with standard Kirchhoff PSDM because of the inherent focusing and the restriction of the back-propagation to the region around the actual reflection point.
An optimized wave equation for seismic modeling and reverse time migration
Authors: Liu Faqi , Zhang Guanquan , Morton Scott A. , Leveille Jacques P.
Published: December 2009

The acoustic wave equation has been widely used for the modeling and reverse time migration of seismic data. Numerical implementation of this equation via finite-difference techniques has established itself as a valuable approach and has long been a favored choice in the industry. To ensure quality results, accurate approximations are required for spatial and time derivatives. Traditionally, they are achieved numerically by using either relatively very fine computation grids or very long finite-difference operators. Otherwise, the numerical error, known as numerical dispersion, is present in the data and contaminates the signals. However, either approach will result in a considerable increase in the computational cost. A simple and computationally low-cost modification to the standard acoustic wave equation is presented to suppress numerical dispersion. This dispersion attenuator is one analogy of the antialiasing operator widely applied in Kirchhoff migration. When the new wave equation is solved numerically using finite-difference schemes, numerical dispersion in the original wave equation is attenuated significantly, leading to a much more accurate finite-difference scheme with little additional computational cost. Numerical tests on both synthetic and field data sets in both two and three dimensions demonstrate that the optimized wave equation dramatically improves the image quality by successfully attenuating dispersive noise. The adaptive application of this new wave equation only increases the computational cost slightly.
Subsalt velocity update and composite imaging using reverse-time-migration based delayed-imaging-time scan
Authors: Wang Bin , Mason Chuck , Guo Manhong , Yoon Kwangjin , Cai Jun , Ji Jean , Li Zhiming
Published: December 2009

Defining the correct velocity is critical for proper subsalt imaging. A subsalt velocity perturbation scan based on wave equation migration is an effective way to update subsalt velocity and has become a standard industry practice. A factor limiting its use is that the cost of generating migration scans remains comparatively high. With the even more expensive reverse-time-migration (RTM) tool progressively becoming a routine, the extension of this subsalt-velocity-perturbation-scan approach to RTM becomes impractical. We propose a new methodology for updating subsalt velocity using an RTM-based scan composed of multiple migrated images. Rather than perturbing the velocity, each image is produced by a variable time-imaging condition. The zero-time imaging condition generates the normal RTM output, and the positive and negative nonzero-time (delayed imaging time, or DIT) imaging condition generates a scan of images called a DIT scan. The generation of the RTM-based DIT scan requires only a single RTM pass. Synthetic and field data examples confirm the effectiveness of this new approach and suggest the DIT scan approach could serve as an efficient alternative or even a replacement to the standard subsalt migration scan approach for RTM.
Imaging by target-oriented wave-equation inversion
Authors: Valenciano Alejandro A. , Biondi Biondo L. , Clapp Robert G.
Published: December 2009

Wave-equation inversion is a powerful technique able to build higher-resolution images with balanced amplitudes in complex subsurface areas relative to migration alone. Wave-equation inversion can be performed in image space without making velocity-model or acquisition-geometry approximations. Our method explicitly computes the least-squares Hessian matrix, defined from the modeling/migration operators, and uses a linear solver to find the solution of the resulting system of equations. One important advantage of the explicit computation of the Hessian, compared to iterative modeling/migration operations schemes, is that most of the work (precomputing the Hessian) is done up front; afterward, different inversion parameters or schemes can be tried at lower cost. Another advantage is that the method canhandle 3D data in a target-oriented fashion. The inversion in the presence of a complex overburden leads to an ill-conditioned system of equations that must be regularized to obtain a stable numerical solution. Regularization can be implemented in the poststack-image domain (zero subsurface offset), where the options for a regularization operator are limited to a customary damping, or in the prestack-image domain (subsurface offset), where a physically inspired regularization operator (differential semblance) can be applied. Though the prestack-image-domain inversion is more expensive than the poststack-image-domain inversion, it can improve the reflectors' continuity into the shadow zones with an enhanced signal-to-noise ratio. Improved subsalt-sediment images in the Sigsbee2b synthetic model and a 3D Gulf of Mexico field data set confirm the benefits of the inversion.
Direct nonlinear inversion of 1D acoustic media using inverse scattering subseries
Authors: Zhang Haiyan , Weglein Arthur B.
Published: December 2009

A task-specific, multiparameter (more than one mechanical property changes across a reflector), direct nonlinear inversion subseries of the inverse-scattering series is derived and tested for an acoustic medium in which velocity and density vary vertically. Task-specific means that terms in the distinct subseries corresponding to tasks for imaging only and inversion only are identified and separated. Direct means there are formulas that solve explicitly for and output the physical properties, without, e.g., search algorithms, model matching and optimization schemes, and proxies that typically characterize indirect methods. Numerical test results with analytic data indicate that one term beyond linear provides added value beyond standard linear techniques, and the improved estimates are valid over a larger range of angles. The direct acoustic inversion is nonlinear. It serves as an important step for new concepts and methods to guide the much more complicated and minimally realistic elastic inverse for exploration seismology target identification purposes.
Elastic imaging and time-lapse migration based on adjoint methods
Authors: Zhu Hejun , Luo Yang , Nissen-Meyer Tarje , Morency Christina , Tromp Jeroen
Published: December 2009

We have drawn connections between imaging in exploration seismology, adjoint methods, and emerging finite-frequency tomography. All of these techniques rely on spatial and temporal constructive interference between observed and simulated waveforms to map locations of structural anomalies. Modern numerical methods and computers have facilitated the accurate and efficient simulation of 3D acoustic, (an)elastic, and poroelastic wave propagation. Using a 2D cross section of the SEG/EAGE salt model, we have determined how such waveform simulations might be harnessed to improve onshore and offshore seismic imaging strategies and capabilities. We have found that the density sensitivity kernel in adjoint tomography is related closely to the imaging principle in exploration seismology, and that in elastic modeling the impedance kernel actually is a better diagnostic tool for reflector identification. The shear- and compressional-wave speed sensitivity kernels in adjoint tomography are related closely to finite-frequency banana-doughnut kernels, and these kernels are well suited for mapping larger-scale structure, i.e., for transmission tomography. These ideas have been substantiated by addressing problems in subsalt time-lapse migration.
Reverse time migration in tilted transversely isotropic (TTI) media
Authors: Fletcher Robin P. , Du Xiang , Fowler Paul J.
Published: December 2009

Reverse time migration (RTM) exhibits great advantages over other imaging methods because it is based on computing numerical solutions to a two-way wave equation. It does not suffer from dip limitation like one-way downward continuation techniques do, thus enabling overturned reflections to be imaged. As well as correctly handling multipathing, RTM has the potential to image internal multiples when the boundaries responsible for generating the multiples are present in the model. In isotropic media, one can use a scalar acoustic wave equation for RTM of pressure data. In anisotropic media, P- and SV-waves are coupled together so, formally, elastic wave equations must be used for RTM. A new wave equation for P-waves is proposed in tilted transversely isotropic (TTI) media that can be solved as part of an acoustic anisotropic RTM algorithm, using standard explicit finite differencing. If the shear velocity along the axis of symmetry is set to zero, stable numerical solutions can be computed for media with a vertical axis of symmetry and [Formula: see text] not less than [Formula: see text]. In TTI media with rapid variations in the direction of the axis of symmetry, setting the shear velocity along the axis of symmetry to zero can cause numerical solutions to become unstable. A solution to this problem is proposed that involves using a small amount of nonzero shear velocity. The amount of shear velocity added is chosen to remove triplications from the SV wavefront and to minimize the anisotropic term of the SV reflection coefficient. We show modeling and high-quality RTM results in complex TTI media using this equation.
Establishing the Predictive Validity of Intentions to Smoke Among Preadolescents and Adolescents Surviving Cancer
Authors: Klosky James L. , Tyc Vida L. , Hum Ashley , Lensing Shelly , Buscemi Joanna , Garces-Webb Danette M. , Hudson Melissa M.
Published: December 2009

Purpose

A significant proportion of adults surviving childhood cancer are smokers. Although these estimated rates of smoking are slightly lower than those in the US population, they remain alarmingly high for this high-risk group. The purpose of this study was to examine the predictive validity of adolescent self-reported smoking intentions for later smoking among childhood cancer survivors.

Patients and Methods

Baseline tobacco intentions were collected from 119 nonsmoking cancer survivors, age 10 to 18 years, who participated in a tobacco-based clinical trial during the late 1990s. Follow-up smoking status was systematically collected annually up to 10 years postintervention (median follow-up, 6.0 years; interquartile range, 3.0 to 6.9 years) as part of clinical survivorship care.

Results

Twenty-seven participants (22.7%) subsequently initiated tobacco use within 5 years of study enrollment. The 5-year cumulative incidence was 29.8% ± 6.0% for those who were susceptible to smoking compared with 12.8% ± 5.4% for those who were committed never smokers (P = .022). Past use (P < .001) and having friends who smoked (P = .038) were also associated (univariate model) with tobacco initiation, and there was a trend for an association for older adolescents (P = .073). Every unit increase on the intentions scale was associated with a 17% increase in the risk for tobacco initiation (P = .002) after adjusting for age group and past tobacco use in a multivariable model.

Conclusion

Because early intentions to smoke are predictive of later tobacco use, survivors as young as 10 years of age who waver in their commitment to remain tobacco abstinent should be targeted for tobacco prevention interventions.
Allogeneic Hematopoietic Stem-Cell Transplantation for Patients 50 Years or Older With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia
Authors: Lim ZiYi , Brand Ronald , Martino Rodrigo , van Biezen Anja , Finke Jürgen , Bacigalupo Andrea , Beelen Dietrich , Devergie Agnes , Alessandrino Emilio , Willemze Roel , Ruutu Tapani , Boogaerts Marc , Falda Michele , Jouet Jean-Pierre , Niederwieser Dietger , Kroger Nicolaus , Mufti Ghulam J. , De Witte Theo M.
Published: December 2009

Purpose

This study was performed to examine the characteristics of transplant activity for patients with myelodysplastic syndromes (MDS) older than 50 years within the European Group for Blood and Marrow Transplantation, and to evaluate the factors predicting outcome within this group of patients.

Patients and Methods

We performed a retrospective multicenter analysis of 1,333 MDS patients age 50 years or older who received transplantation within the EBMT since 1998. The median recipient age was 56 years, with 884 patients (66%) age 50 to 60 years and 449 (34%) patients older than 60 years. There were 811 HLA-matched sibling (61%) and 522 (39%) unrelated donor transplants. Five hundred patients (38%) received standard myeloablative conditioning (SMC), and 833 (62%) received reduced intensity conditioning (RIC).

Results

The 4-year estimate for overall survival of the whole cohort was 31%. On multivariate analysis, use of RIC (hazard ratio [HR], 1.44; 95% CI, 1.13 to 1.84; P < .01) and advanced disease stage at transplantation (HR, 1.51; 95% CI, 1.18 to 1.93; P < .01) were associated with an increased relapse rate. In contrast, advanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P = .01), use of an unrelated donor (P = .03), and RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P = .03) were independent variables associated with nonrelapse mortality. Advanced disease stage at transplantation (HR, 1.55; 95% CI, 1.32 to 1.83; P < .01) was the major independent variable associated with an inferior 4-year overall survival.

Conclusion

Allogeneic hematopoietic stem-cell transplantation remains a potential curative therapeutic option for many older patients with MDS. In this analysis, disease stage at time of transplantation, but not recipient age or the intensity of the conditioning regimens, was the most important factor influencing outcomes.
Association Between Disease-Free Survival and Overall Survival When Survival Is Prolonged After Recurrence in Patients Receiving Cytotoxic Adjuvant Therapy for Colon Cancer: Simulations Based on the 20,800 Patient ACCENT Data Set
Authors: de Gramont Aimery , Hubbard Joleen , Shi Qian , O'Connell Michael J. , Buyse Marc , Benedetti Jacqueline , Bot Brian , O'Callaghan Chris , Yothers Greg , Goldberg Richard M. , Blanke Charles D. , Benson Al , Deng Qiqi , Alberts Steven R. , Andre Thierry , Wolmark Norman , Grothey Axel , Sargent Daniel
Published: December 2009

Purpose

We previously validated disease-free survival (DFS) as a surrogate for overall survival (OS) in fluorouracil-based adjuvant colon cancer clinical trials. New therapies have extended survival after recurrence from 1 to approximately 2 years. We examined the possible impact of this improvement on the DFS/OS association.

Methods

The Adjuvant Colon Cancer Endpoints (ACCENT) data set of 20,898 patients was analyzed. In an exploratory fashion, time from recurrence to death in patients experiencing recurrence was extended using several algorithms, and the association of DFS after 3 years of median follow-up and OS after varying lengths of follow-up (median of 5, 6, and 7 years) was assessed.

Results

Seven thousand four hundred two patients (35%) experienced recurrence. Median time from recurrence to death was 24 months in the hypothetical data sets. When times from recurrence to death were doubled, the association between treatment effects on DFS and 5-year OS was modest (R2 = 0.51 for both 2- and 3-year DFS) but remained strong for DFS and 6-year OS (R2 = 0.67 for both 2- and 3-year DFS) and 7-year OS (R2 = 0.70 for both 2- and 3-year DFS). The reduced DFS/OS association with extended survival after recurrence was greater in stage II than stage III patients. Multiple simulations provided consistent findings.

Conclusion

Extended survival after recurrence reduces the association between treatment effects on 3-year DFS and 5-year OS, particularly in stage II patients; longer follow-up strengthens the association. In modern adjuvant trials, 6 or 7 years may be required to demonstrate OS improvements, further supporting DFS as the preferred primary end point for future adjuvant colon cancer clinical trials.
Flavopiridol, Fludarabine, and Rituximab in Mantle Cell Lymphoma and Indolent B-Cell Lymphoproliferative Disorders
Authors: Lin Thomas S. , Blum Kristie A. , Fischer Diane Beth , Mitchell Sarah M. , Ruppert Amy S. , Porcu Pierluigi , Kraut Eric H. , Baiocchi Robert A. , Moran Mollie E. , Johnson Amy J. , Schaaf Larry J. , Grever Michael R. , Byrd John C.
Published: December 2009

Purpose

Flavopiridol downmodulates antiapoptotic proteins associated with resistance to fludarabine and rituximab and is effective against p53-mutated chronic lymphocytic leukemia (CLL). We conducted a phase I study of flavopiridol, fludarabine, and rituximab (FFR) in patients with mantle-cell lymphoma (MCL), indolent B-cell non-Hodgkin's lymphomas (B-NHL), and CLL to determine the activity of FFR.

Patients and Methods

Therapy included fludarabine 25 mg/m2 intravenously (IV) days 1 to 5 and rituximab 375 mg/m2 day 1 every 28 days for 6 cycles. We administered flavopiridol 50 mg/m2 by 1-hour IV bolus (IVB) day 1 (n = 15); day 1 to 2 (n = 6); 20 mg/m2 30-minute IVB + 20 mg/m2 4-hour IV infusion (n = 3); or 30 mg/m2 + 30 mg/m2 (n = 14).

Results

Thirty-eight patients (median age, 62 years) with MCL (n = 10); indolent B-NHL including follicular (n = 9), marginal zone (n = 4), lymphoplasmacytic (n = 1), or small lymphocytic lymphoma (n = 3); and CLL (n = 11), were enrolled. Twenty-two patients were previously untreated; 16 had received one to two prior therapies. Two patients in cohort 2 developed grade 3 dose-limiting toxicity (seizures, renal insufficiency). The median number of treatment cycles was 4, with cytopenias (n = 10) and fatigue (n = 3) the most common reasons for early discontinuation. Overall response rate was 82% (complete response, 50%; unconfirmed complete response, 5%; partial response, 26%), including 80% of patients with MCL (median age, 68; seven complete responses, one partial response). Median progression-free survival (PFS) was 25.6 months. Median PFS of patients with nonblastoid variant MCL (n = 8) was 35.9 months.

Conclusion

FFR was active in MCL, indolent B-NHL, and CLL and should be studied for older patients with MCL who are not candidates for aggressive chemotherapy.
Pathology Review of Thin Melanoma and Melanoma in Situ in a Multidisciplinary Melanoma Clinic: Impact on Treatment Decisions
Authors: Santillan Alfredo A. , Messina Jane L. , Marzban Suroosh S. , Crespo Gema , Sondak Vernon K. , Zager Jonathan S.
Published: December 2009

Purpose

Patients with thin melanoma (≤ 1.0 mm) and melanoma in situ (MIS) represent the majority of newly diagnosed melanoma. We estimated the impact of expert review of outside pathology material on the staging and thus treatment decisions affecting patients referred to a multidisciplinary clinic with early-stage melanoma.

Patients and Methods

We studied patients with a diagnosis of thin melanoma or MIS referred to H. Lee Moffitt Cancer Center from 2006 to 2009. After comparing the referring laboratory and in-house dermatopathologic interpretations, we calculated any differences in diagnosis and tumor staging and the potential impact of differences in diagnosis and staging on prognosis and surgical treatment using the National Comprehensive Cancer Network clinical guidelines.

Results

The overall pathologic discordance rate in diagnosis was 4% (15 of 420 patients; 95% CI, 2% to 6%). The overall change in tumor staging rate was 24% (97 of 405 patients; 95% CI, 20% to 28%). Pathology review led to changes in surgical excision margins in 12% of patients (52 of 420 patients; 95% CI, 9% to 16%) and in the decision about whether to perform a sentinel lymph node biopsy in 16% of patients (67 of 420 patients; 95% CI, 13% to 20%). Key pathologic factors, particularly mitotic rate, were frequently missing from outside pathology reports.

Conclusion

Our data suggest that review of thin melanoma or MIS by an expert dermatopathologist results in frequent, clinically meaningful alterations in diagnosis, staging, prognosis, and surgical treatment. Referral of these patients to a multidisciplinary melanoma clinic is appropriate, and management of such patients should include review of the biopsy whenever feasible.
Phase II Trial of Infusional Fluorouracil, Irinotecan, and Bevacizumab for Metastatic Colorectal Cancer: Efficacy and Circulating Angiogenic Biomarkers Associated With Therapeutic Resistance
Authors: Kopetz Scott , Hoff Paulo M. , Morris Jeffrey S. , Wolff Robert A. , Eng Cathy , Glover Katrina Y. , Adinin Rosie , Overman Michael J. , Valero Vincete , Wen Sijin , Lieu Christopher , Yan Shaoyu , Tran Hai T. , Ellis Lee M. , Abbruzzese James L. , Heymach John V.
Published: December 2009

Purpose

We investigated the efficacy of fluorouracil (FU), leucovorin, irinotecan, and bevacizumab (FOLFIRI + B) in a phase II trial in patients previously untreated for metastatic colorectal cancer (mCRC), and changes during treatment in plasma cytokines and angiogenic factors (CAFs) as potential markers of treatment response and therapeutic resistance.

Patients and Methods

We conducted a phase II, two-institution trial of FOLFIRI + B. Each 14-day cycle consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m2), bolus FU (400 mg/m2), and leucovorin (400 mg/m2) followed by a 46-hour infusion of FU (2,400 mg/m2). Levels of 37 CAFs were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, during treatment, and at the time of progressive disease (PD).

Results

Forty-three patients were enrolled. Median progression-free survival (PFS), the primary end point of the study, was 12.8 months. Median overall survival was 31.3 months, with a response rate of 65%. Elevated interleukin-8 at baseline was associated with a shorter PFS (11 v 15.1 months, P = .03). Before the radiographic development of PD, several CAFs associated with angiogenesis and myeloid recruitment increased compared to baseline, including basic fibroblast growth factor (P = .046), hepatocyte growth factor (P = .046), placental growth factor (P < .001), stromal-derived factor-1 (P = .04), and macrophage chemoattractant protein-3 (P < .001).

Conclusion

Efficacy and tolerability of FOLFIRI + B appeared favorable to historical controls in this single arm study. Before radiographic progression, there was a shift in balance of CAFs, with a rise in alternate pro-angiogenic cytokines and myeloid recruitment factors in subsets of patients that may represent mechanisms of resistance.
Screening for Founder Mutations in BRCA1 and BRCA2 in Unselected Jewish Women
Authors: Metcalfe Kelly A. , Poll Aletta , Royer Robert , Llacuachaqui Marcia , Tulman Anna , Sun Ping , Narod Steven A.
Published: December 2009

Purpose

There are two mutations in BRCA1 and one mutation in BRCA2 that are present in up to 2.5% of Ashkenazi Jewish women. Current guidelines for testing stipulate that a personal or family history of cancer be present to be eligible for testing. To date, population screening in this population has not been suggested. However, this may be rational. Little is known about the appropriateness of testing guidelines for the Jewish population or the level of interest in testing.

Methods

Eligible subjects were women who self-identified as Jewish, who were between the ages of 25 and 80 years, and who resided in Ontario. Subjects were recruited through an article in a national newspaper. Women were asked to complete a study questionnaire and a family history questionnaire and to provide a blood or saliva sample. The risk of carrying a BRCA mutation was estimated for each woman.

Results

A total of 2,080 women were enrolled onto the study. The overall mutation prevalence was 1.1% (0.5% for BRCA1 and 0.6% for BRCA2). Among the 22 mutation carriers, the mean estimate of carrying a BRCA mutation was 3.9%. Ten (45%) of the 22 women met the current Ontario Ministry of Health Guidelines criteria for testing.

Conclusion

There is considerable interest for genetic testing among Jewish women at low risk of carrying a mutation. However, many women with mutations are ineligible for genetic testing under current guidelines. Approximately 1% of Jewish women carry a BRCA mutation, and these women should be considered to be candidates for genetic testing.