Showing papers by "Vanderbilt University published in 2003"

The International HapMap Project

Abstract: The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.

Design Experiments in Educational Research

Abstract: In this article, the authors first indicate the range of purposes and the variety of settings in which design experiments have been conducted and then delineate five crosscutting features that collectively differentiate design experiments from other methodologies. Design experiments have both a pragmatic bent—“engineering” particular forms of learning—and a theoretical orientation—developing domain-specific theories by systematically studying those forms of learning and the means of supporting them. The authors clarify what is involved in preparing for and carrying out a design experiment, and in conducting a retrospective analysis of the extensive, longitudinal data sets generated during an experiment. Logistical issues, issues of measure, the importance of working through the data systematically, and the need to be explicit about the criteria for making inferences are discussed.

Testing mediational models with longitudinal data: questions and tips in the use of structural equation modeling.

Abstract: R. M. Baron and D. A. Kenny (1986; see record 1987-13085-001) provided clarion conceptual and methodological guidelines for testing mediational models with cross-sectional data. Graduating from cross-sectional to longitudinal designs enables researchers to make more rigorous inferences about the causal relations implied by such models. In this transition, misconceptions and erroneous assumptions are the norm. First, we describe some of the questions that arise (and misconceptions that sometimes emerge) in longitudinal tests of mediational models. We also provide a collection of tips for structural equation modeling (SEM) of mediational processes. Finally, we suggest a series of 5 steps when using SEM to test mediational processes in longitudinal designs: testing the measurement model, testing for added components, testing for omitted paths, testing the stationarity assumption, and estimating the mediational effects.

Epithelial-mesenchymal transition and its implications for fibrosis.

Abstract: Epithelial to mesenchymal transition (EMT) is a central mechanism for diversifying the cells found in complex tissues. This dynamic process helps organize the formation of the body plan, and while EMT is well studied in the context of embryonic development, it also plays a role in the genesis of fibroblasts during organ fibrosis in adult tissues. Emerging evidence from studies of renal fibrosis suggests that more than a third of all disease-related fibroblasts originate from tubular epithelia at the site of injury. This review highlights recent advances in the process of EMT signaling in health and disease and how it may be attenuated or reversed by selective cytokines and growth factors.

Efficacy of Gefitinib, an Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Symptomatic Patients with Non-Small Cell Lung Cancer: A Randomized Trial

Abstract: ContextMore persons in the United States die from non–small cell lung cancer (NSCLC) than from breast, colorectal, and prostate cancer combined. In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors that express the epidermal growth factor receptor (EGFR), a mediator of cell signaling, and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib.ObjectiveTo assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib.Design, Setting, and PatientsDouble-blind, randomized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers. Patients (N = 221) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens.InterventionDaily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching placebo).Main Outcome MeasuresImprovement of NSCLC symptoms (2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion size on imaging studies).ResultsOf 221 patients enrolled, 216 received gefitinib as randomized. Symptoms of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving 500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving 250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg. Symptoms improved in 96% of patients with partial radiographic responses. The overall survival at 1 year was 25%. There were no significant differences between the 250-mg and 500-mg doses in rates of symptom improvement (P = .26), radiographic tumor regression (P = .51), and projected 1-year survival (P = .54). The 500-mg dose was associated more frequently with transient acne-like rash (P = .04) and diarrhea (P = .006).ConclusionsGefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved disease-related symptoms and induced radiographic tumor regressions in patients with NSCLC persisting after chemotherapy.

Species-Level Paraphyly and Polyphyly: Frequency, Causes, and Consequences, with Insights from Animal Mitochondrial DNA

Abstract: ▪ Abstract Many uses of gene trees implicitly assume that nominal species are monophyletic in their alleles at the study locus. However, in well-sampled gene trees, certain alleles in one species may appear more closely related to alleles from different species than to other conspecific alleles. Such deviations from species-level monophyly have a variety of causes and may lead to erroneous evolutionary interpretations if undetected. The present paper describes the causes and consequences of these paraphyletic and polyphyletic patterns. It also provides a detailed literature survey of mitochondrial DNA studies on low-level animal phylogeny and phylogeography, results from which reveal the frequency of nonmonophyly and patterns of interpretation and sampling. This survey detected species-level paraphyly or polyphyly in 23% of 2319 assayed species, demonstrating this phenomenon to be statistically supported, taxonomically widespread, and far more common than generally recognized. Our findings call for increa...

The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia.

Abstract: background Benign prostatic hyperplasia is commonly treated with alpha-adrenergic–receptor antagonists (alpha-blockers) or 5 a -reductase inhibitors. The long-term effect of these drugs, singly or combined, on the risk of clinical progression is unknown. methods We conducted a long-term, double-blind trial (mean follow-up, 4.5 years) involving 3047 men to compare the effects of placebo, doxazosin, finasteride, and combination therapy on measures of the clinical progression of benign prostatic hyperplasia. results The risk of overall clinical progression — defined as an increase above base line of at least 4 points in the American Urological Association symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection — was significantly reduced by doxazosin (39 percent risk reduction, P<0.001) and finasteride (34 percent risk reduction, P=0.002), as compared with placebo. The reduction in risk associated with combination therapy (66 percent for the comparison with placebo, P<0.001) was significantly greater than that associated with doxazosin (P<0.001) or finasteride (P<0.001) alone. The risks of acute urinary retention and the need for invasive therapy were significantly reduced by combination therapy (P<0.001) and finasteride (P<0.001) but not by doxazosin. Doxazosin (P<0.001), finasteride (P =0.001), and combination therapy (P<0.001) each resulted in significant improvement in symptom scores, with combination therapy being superior to both doxazosin (P=0.006) and finasteride (P<0.001) alone. conclusions Long-term combination therapy with doxazosin and finasteride was safe and reduced the risk of overall clinical progression of benign prostatic hyperplasia significantly more than did treatment with either drug alone. Combination therapy and finasteride alone reduced the long-term risk of acute urinary retention and the need for invasive therapy.

New Constraints on ΩM, ΩΛ, and w from an Independent Set of 11 High-Redshift Supernovae Observed with the Hubble Space Telescope*

Abstract: We report measurements of $\Omega_M$, $\Omega_\Lambda$, and w from eleven supernovae at z=0.36-0.86 with high-quality lightcurves measured using WFPC-2 on the HST. This is an independent set of high-redshift supernovae that confirms previous supernova evidence for an accelerating Universe. Combined with earlier Supernova Cosmology Project data, the new supernovae yield a flat-universe measurement of the mass density $\Omega_M=0.25^{+0.07}_{-0.06}$ (statistical) $\pm0.04$ (identified systematics), or equivalently, a cosmological constant of $\Omega_\Lambda=0.75^{+0.06}_{-0.07}$ (statistical) $\pm0.04$ (identified systematics). When the supernova results are combined with independent flat-universe measurements of $\Omega_M$ from CMB and galaxy redshift distortion data, they provide a measurement of $w=-1.05^{+0.15}_{-0.20}$ (statistical) $\pm0.09$ (identified systematic), if w is assumed to be constant in time. The new data offer greatly improved color measurements of the high-redshift supernovae, and hence improved host-galaxy extinction estimates. These extinction measurements show no anomalous negative E(B-V) at high redshift. The precision of the measurements is such that it is possible to perform a host-galaxy extinction correction directly for individual supernovae without any assumptions or priors on the parent E(B-V) distribution. Our cosmological fits using full extinction corrections confirm that dark energy is required with $P(\Omega_\Lambda>0)>0.99$, a result consistent with previous and current supernova analyses which rely upon the identification of a low-extinction subset or prior assumptions concerning the intrinsic extinction distribution.

Evaluating Medication Effects Outside of Clinical Trials: New-User Designs

Abstract: Recent clinical trials demonstrating that hormone replacement therapy (HRT) does not prevent coronary heart disease in women have again raised doubts concerning observational studies. Although much of the explanation probably lies in what might be called the "healthy HRT user" effect, another contributing factor may be that most observational studies included many prevalent users: women taking HRT for some time before study follow-up began. This practice can cause two types of bias, both of which plausibly may have contributed to the discrepancy between observational and randomized studies. First, prevalent users are "survivors" of the early period of pharmacotherapy, which can introduce substantial bias if risk varies with time, just as in studies of operative procedures that enroll patients after they have survived surgery. This article provides several examples of medications for which the hazard function varies with time and thus would be subject to prevalent user bias. Second, covariates for drug users at study entry often are plausibly affected by the drug itself. Investigators often do not adjust for these factors on the causal pathway, which may introduce confounding. A new-user design eliminates these biases by restricting the analysis to persons under observation at the start of the current course of treatment. This article thus argues that such designs should be used more frequently in pharmacoepidemiology.

Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS).

Abstract: ContextGoal-directed delivery of sedative and analgesic medications is recommended as standard care in intensive care units (ICUs) because of the impact these medications have on ventilator weaning and ICU length of stay, but few of the available sedation scales have been appropriately tested for reliability and validity.ObjectiveTo test the reliability and validity of the Richmond Agitation-Sedation Scale (RASS).DesignProspective cohort study.SettingAdult medical and coronary ICUs of a university-based medical center.ParticipantsThirty-eight medical ICU patients enrolled for reliability testing (46% receiving mechanical ventilation) from July 21, 1999, to September 7, 1999, and an independent cohort of 275 patients receiving mechanical ventilation were enrolled for validity testing from February 1, 2000, to May 3, 2001.Main Outcome MeasuresInterrater reliability of the RASS, Glasgow Coma Scale (GCS), and Ramsay Scale (RS); validity of the RASS correlated with reference standard ratings, assessments of content of consciousness, GCS scores, doses of sedatives and analgesics, and bispectral electroencephalography.ResultsIn 290-paired observations by nurses, results of both the RASS and RS demonstrated excellent interrater reliability (weighted κ, 0.91 and 0.94, respectively), which were both superior to the GCS (weighted κ, 0.64; P<.001 for both comparisons). Criterion validity was tested in 411-paired observations in the first 96 patients of the validation cohort, in whom the RASS showed significant differences between levels of consciousness (P<.001 for all) and correctly identified fluctuations within patients over time (P<.001). In addition, 5 methods were used to test the construct validity of the RASS, including correlation with an attention screening examination (r = 0.78, P<.001), GCS scores (r = 0.91, P<.001), quantity of different psychoactive medication dosages 8 hours prior to assessment (eg, lorazepam: r = − 0.31, P<.001), successful extubation (P = .07), and bispectral electroencephalography (r = 0.63, P<.001). Face validity was demonstrated via a survey of 26 critical care nurses, which the results showed that 92% agreed or strongly agreed with the RASS scoring scheme, and 81% agreed or strongly agreed that the instrument provided a consensus for goal-directed delivery of medications.ConclusionsThe RASS demonstrated excellent interrater reliability and criterion, construct, and face validity. This is the first sedation scale to be validated for its ability to detect changes in sedation status over consecutive days of ICU care, against constructs of level of consciousness and delirium, and correlated with the administered dose of sedative and analgesic medications.

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

Abstract: Motivation: Polymorphisms in human genes are being described in remarkable numbers. Determining which polymorphisms and which environmental factors are associated with common, complex diseases has become a daunting task. This is partly because the effect of any single genetic variation will likely be dependent on other genetic variations (gene–gene interaction or epistasis) and environmental factors (gene–environment interaction). Detecting and characterizing interactions among multiple factors is both a statistical and a computational challenge. To address this problem, we have developed am ultifactor dimensionality reduction (MDR) method for collapsing high-dimensional genetic data into a single dimension thus permitting interactions to be detected in relatively small sample sizes. In this paper, we describe the MDR approach and an MDR software package. Results: We developed a program that integrates MDR with a cross-validation strategy for estimating the classification and prediction error of multifactor models. The software can be used to analyze interactions among 2–15 genetic and/or environmental factors. The dataset may contain up to 500 total variables and a maximum of 4000 study subjects.

You Are What They Eat: The Infulence of Reference Groups on Consumers' Connections to Brands

Abstract: The set of associations consumers have about a brand is an important component of brand equity. This paper focuses on reference groups as a source of brand associations, which can be linked to one's mental representation of self to meet self-verification or self-enhancement goals. We conceptualize this linkage at an aggregate level in terms of self-brand connections, i.e., the extent to which individuals have incorporated a brand into their self-concept. Two studies show that brands used by member groups and aspiration groups can become connected to consumers' mental representation of self as they use these brands to define and create their self-concepts. Results from Experiment 1 show that the degree to which member group and aspiration group usage influences individual self-brand connections is contingent upon the degree to which the individual belongs to a member group or wishes to belong to an aspiration group. Experiment 2 finds that for individuals with self-enhancement goals, aspiration group brand use has a greater impact on self-brand connections; for individuals with self-verification goals, on the other hand, member group use has a greater impact.

Hot and cold granites? Implications of zircon saturation temperatures and preservation of inheritance

Abstract: Zircon saturation temperatures ( T Zr) calculated from bulk-rock compositions provide minimum estimates of temperature if the magma was undersaturated, but maxima if it was saturated. For plutons with abundant inherited zircon, T Zr provides a useful estimate of initial magma temperature at the source, an important parameter that is otherwise inaccessible. Among 54 investigated plutons, there is a clear distinction between T Zr for inheritance-rich (mean 766 °C) and inheritance-poor (mean 837 °C) granitoids. The latter were probably undersaturated in zircon at the source, and hence the calculated T Zr is likely to be an underestimate of their initial temperature. These data suggest fundamentally different mechanisms of magma generation, transport, and emplacement. “Hot” felsic magmas with minimal inheritance probably require advective heat input into the crust, are crystal poor, and readily erupt, whereas “cold,” inheritance-rich magmas require fluid influx, are richer in crystals, and are unlikely to erupt.

Basic mechanisms and modeling of single-event upset in digital microelectronics

Abstract: Physical mechanisms responsible for nondestructive single-event effects in digital microelectronics are reviewed, concentrating on silicon MOS devices and integrated circuits. A brief historical overview of single-event effects in space and terrestrial systems is given, and upset mechanisms in dynamic random access memories, static random access memories, and combinational logic are detailed. Techniques for mitigating single-event upset are described, as well as methods for predicting device and circuit single-event response using computer simulations. The impact of technology trends on single-event susceptibility and future areas of concern are explored.

Responsiveness-to-Intervention: Definitions, Evidence, and Implications for the Learning Disabilities Construct.

Abstract: Longstanding concern about how learning disabilities (LD) are defined and identified, coupled with recent efforts in Washington, DC to eliminate IQ-achievement discrepancy as an LD marker, have led to serious public discussion about alternative identification methods. The most popular of the alternatives is responsiveness-to-intervention (RTI), of which there are two basic versions: the “problem-solving” model and the “standard-protocol” approach. The authors describe both types, review empirical evidence bearing on their effectiveness and feasibility, and conclude that more needs to be understood before RTI may be viewed as a valid means of identifying students with LD.

Automated Method for Subtraction of Fluorescence from Biological Raman Spectra

Abstract: One of the challenges of using Raman spectroscopy for biological applications is the inherent fluorescence generated by many biological molecules that underlies the measured spectra. This fluorescence can sometimes be several orders of magnitude more intense than the weak Raman scatter, and its presence must be minimized in order to resolve and analyze the Raman spectrum. Several techniques involving hardware and software have been devised for this purpose; these include the use of wavelength shifting, time gating, frequency-domain filtering, first- and second-order derivatives, and simple curve fitting of the broadband variation with a high-order polynomial. Of these, polynomial fitting has been found to be a simple but effective method. However, this technique typically requires user intervention and thus is time consuming and prone to variability. An automated method for fluorescence subtraction, based on a modification to least-squares polynomial curve fitting, is described. Results indicate that the presented automated method is proficient in fluorescence subtraction, repeatability, and in retention of Raman spectral lineshapes.

A linear time algorithm for computing exact Euclidean distance transforms of binary images in arbitrary dimensions

Abstract: A sequential algorithm is presented for computing the exact Euclidean distance transform (DT) of a k-dimensional binary image in time linear in the total number of voxels N. The algorithm, which is based on dimensionality reduction and partial Voronoi diagram construction, can be used for computing the DT for a wide class of distance functions, including the L/sub p/ and chamfer metrics. At each dimension level, the DT is computed by constructing the intersection of the Voronoi diagram whose sites are the feature voxels with each row of the image. This construction is performed efficiently by using the DT in the next lower dimension. The correctness and linear time complexity are demonstrated analytically and verified experimentally. The algorithm may be of practical value since it is relatively simple and easy to implement and it is relatively fast (not only does it run in O(N) time but the time constant is small). A simple modification of the algorithm computes the weighted Euclidean DT, which is useful for images with anisotropic voxel dimensions. A parallel version of the algorithm runs in O(N/p) time with p processors.

Premature coronary-artery atherosclerosis in systemic lupus erythematosus.

Abstract: Background Premature coronary artery disease is a major cause of illness and death in patients with systemic lupus erythematosus, but little is known about the prevalence, extent, and causes of coronary-artery atherosclerosis. Methods We used electron-beam computed tomography to screen for the presence of coronary-artery calcification in 65 patients with systemic lupus erythematosus (mean [±SD] age, 40.3±11.6 years) and 69 control subjects (mean age, 42.7±12.6 years) with no history of coronary artery disease. When calcification was detected, the extent was measured by means of the Agatston score. The frequency of risk factors for coronary artery disease was compared in patients and controls, and the relation between the patients' clinical characteristics and the presence or absence of coronary-artery calcification was examined. Results The two groups were similar with respect to age, race, and sex. Coronary-artery calcification was more frequent in patients with lupus (20 of 65 patients) than in control ...

Alport's Syndrome, Goodpasture's Syndrome, and Type IV Collagen

Abstract: Defects in type IV collagen, a collagenous protein involved in the formation of basement membranes, have been implicated in hereditary Alport's syndrome and acquired Goodpasture's syndrome. Mutations in genes corresponding to the building blocks of type IV collagen cause Alport's syndrome, whereas autoantibodies against structures that are usually hidden in the recesses of collagen IV cause Goodpasture's syndrome.

Serotonin receptors: their key role in drugs to treat schizophrenia.

Abstract: Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are usually referred to as atypical APDs because of their ability to achieve an antipsychotic effect with lower rates of extrapyramidal side effects (EPS) compared to first-generation APDs such as haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol. Exp. Ther. 251 (1989) 238] that potent 5-HT2A receptor antagonism together with weak dopamine (DA) D2 receptor antagonism are the principal pharmacologic features that differentiate clozapine and other apparent atypical APDs from first-generation typical APD. This hypothesis is consistent with the atypical features of quetiapine, olanzapine, risperidone, and ziprasidone, which are the most common treatments for schizophrenia in the United States and many other countries, as well as a large number of compounds in various stages of development. Subsequent research showed that 5-HT1A agonism may be an important consequence of 5-HT2A antagonism and that substitution of 5-HT1A agonism for 5-HT2A antagonism may also produce an atypical APD drug when coupled with weak D2 antagonism. Aripiprazole, the most recently introduced atypical APD, and a D2 receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast, the alternative "fast-off" hypothesis of Kapur and Seeman [Am. J. Psychiatry 158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with the "slow" off rate of most atypical APDs, including olanzapine, risperidone and ziprasidone. 5-HT2A and 5-HT1A receptors located on glutamatergic pyramidal neurons in the cortex and hippocampus, 5-HT2A receptors on the cell bodies of DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons in the cortex and hippocampus, and 5-HT1A receptors in the raphe nuclei are likely to be important sites of action of the atypical APDs. At the same time, evidence has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors for some of the effects of some of the current APDs. Thus, 5-HT has joined DA as a critical target for developing effective APDs and led to the search for novel drugs with complex pharmacology, ending the exclusive search for single-receptor targets, e.g., the D3 or D4 receptor, and drugs that are selective for them.

A core function for p120-catenin in cadherin turnover

Abstract: p120-catenin stabilizes epithelial cadherin (E-cadherin) in SW48 cells, but the mechanism has not been established. Here, we show that p120 acts at the cell surface to control cadherin turnover, thereby regulating cadherin levels. p120 knockdown by siRNA expression resulted in dose-dependent elimination of epithelial, placental, neuronal, and vascular endothelial cadherins, and complete loss of cell–cell adhesion. ARVCF and δ-catenin were functionally redundant, suggesting that proper cadherin-dependent adhesion requires the presence of at least one p120 family member. The data reveal a core function of p120 in cadherin complexes, and strongly predict a dose-dependent loss of E-cadherin in tumors that partially or completely down-regulate p120.

Facial and vocal expressions of emotion.

Abstract: A flurry of theoretical and empirical work concerning the production of and response to facial and vocal expressions has occurred in the past decade. That emotional expressions express emotions is a tautology but may not be a fact. Debates have centered on universality, the nature of emotion, and the link between emotions and expressions. Modern evolutionary theory is informing more models, emphasizing that expressions are directed at a receiver, that the interests of sender and receiver can conflict, that there are many determinants of sending an expression in addition to emotion, that expressions influence the receiver in a variety of ways, and that the receiver's response is more than simply decoding a message.