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This paper introduces flowthrough centrality, a node centrality measure determined from the hierarchical maximum concurrent flow problem (HMCFP). Based upon the extent to which a node is acting as a hub within a network, this centrality measure is defined to be the fraction of the flow passing through the node to the total flow capacity of the node. Flowthrough centrality is compared to the commonly-used centralities of closeness centrality, betweenness centrality, and flow betweenness centrality, as well as to stable betweenness centrality to measure the stability (i.e., accuracy) of the centralities when knowledge of the network topology is incomplete or in transition. Perturbations do not alter the flowthrough centrality values of nodes that are based upon flow as much as they do other types of centrality values that are based upon geodesics. The flowthrough centrality measure overcomes the problem of overstating or understating the roles that significant actors play in social networks. The flowthrough centrality is canonical in that it is determined from a natural, realized flow universally applicable to all networks.

Much has been made of the flipped classroom as an approach to teaching, and its effect on student learning. The volume of material showing that the flipped classroom technique helps students better learn and better retain material is increasing at a rapid pace. Coupled with this technique is active learning in the classroom. There are many ways of “flipping the classroom.” The particular realization of the flipped classroom that we discuss in this article is based on a method called “Just-in-Time Teaching (JiTT).” However, JiTT, in particular, and the flipped classroom, in general, is not just about watching videos before class, or doing activities during class time. JiTT includes assigning short, web-based questions to students based on previously viewed material. Typically, Internet-based questions are constructed to elicit common misunderstandings from the students, so that the instructor can correct such misunderstandings immediately in the next class period, hence the name, “Just-in-Time Teac...

The prevalence of renal insufficiency in patients with chronic liver disease is unknown; furthermore, no specific etiology has been demonstrated to be the predominant cause of renal insufficiency in these patients, and no factors predicting it have been identified.

Flow cytometry (FCM) is a fluorescence-based single-cell experimental technology that is routinely applied in biomedical research for identifying cellular biomarkers of normal physiological responses and abnormal disease states. While many computational methods have been developed that focus on identifying cell populations in individual FCM samples, very few have addressed how the identified cell populations can be matched across samples for comparative analysis. This article presents FlowMap-FR, a novel method for cell population mapping across FCM samples. FlowMap-FR is based on the Friedman-Rafsky nonparametric test statistic (FR statistic), which quantifies the equivalence of multivariate distributions. As applied to FCM data by FlowMap-FR, the FR statistic objectively quantifies the similarity between cell populations based on the shapes, sizes, and positions of fluorescence data distributions in the multidimensional feature space. To test and evaluate the performance of FlowMap-FR, we simulated the kinds of biological and technical sample variations that are commonly observed in FCM data. The results show that FlowMap-FR is able to effectively identify equivalent cell populations between samples under scenarios of proportion differences and modest position shifts. As a statistical test, FlowMap-FR can be used to determine whether the expression of a cellular marker is statistically different between two cell populations, suggesting candidates for new cellular phenotypes by providing an objective statistical measure. In addition, FlowMap-FR can indicate situations in which inappropriate splitting or merging of cell populations has occurred during gating procedures. We compared the FR statistic with the symmetric version of Kullback-Leibler divergence measure used in a previous population matching method with both simulated and real data. The FR statistic outperforms the symmetric version of KL-distance in distinguishing equivalent from nonequivalent cell populations. FlowMap-FR was also employed as a distance metric to match cell populations delineated by manual gating across 30 FCM samples from a benchmark FlowCAP data set. An F-measure of 0.88 was obtained, indicating high precision and recall of the FR-based population matching results. FlowMap-FR has been implemented as a standalone R/Bioconductor package so that it can be easily incorporated into current FCM data analytical workflows.

The abstraction augmented Markov model (AAMM) is an extension of a Markov model that can be used for the analysis of genetic sequences. It is developed using the frequencies of all possible consecutive words with same length (p-mers). This article will review the theory behind AAMM and apply the theory behind AAMM in metagenomic classification.

Categorical time series are time-sequenced data in which the values at each time point are categories rather than measurements. A categorical time series is considered stationary if the marginal distribution of the data is constant over the time period for which it was gathered and the correlation between successive values is a function only of their distance from each other and not of their position in the series. However, there are many examples of categorical series which do not fit this rather strong definition of stationarity. Such data show various nonstationary behavior, such as a change in the probability of the occurrence of one or more categories. In this paper, we introduce an algorithm which corrects for nonstationarity in categorical time series. The algorithm produces series which are not stationary in the traditional sense often used for stationary categorical time series. The form of stationarity is weaker but still useful for parameter estimation. Simulation results show that this simple algorithm applied to a DAR(1) model can dramatically improve the parameter estimates.

Pruritus is defined as the second order of nociception, the first being pain; thus, there is a rationale to study gabapentin, a drug that increases the threshold to experience nociception. The aim of this double-blind, randomized, placebo-controlled trial was to study the effect of gabapentin on the perception of pruritus and its behavioral manifestation, scratching, in cholestasis. The participants were 16 women with chronic liver disease and chronic pruritus. Hourly scratching activity (HSA) was continuously recorded for up to 48 hours at baseline and on treatment for at least 4 weeks in an inpatient setting. The perception of pruritus was assessed by interviews and by a visual analog score (VAS) of pruritus recorded every hour while patients were awake. Patients were randomized to the study drug (gabapentin or placebo) at a starting dose of 300 mg orally per day in divided doses to a maximum of 2,400 mg or until relief from pruritus. Gabapentin was associated with an increase in mean HSA, in contrast to the placebo, which was associated with a decrease. The mean VAS decreased significantly among those taking the placebo and in some patients on gabapentin. In conclusion, gabapentin did not provide a significant therapeutic advantage over the placebo; in fact, it was associated with an increase in the perception of pruritus and in HSA in some patients.

The human T-cell lymphotropic virus type-1 (HTLV-1) infects CD4+ T cells and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive lymphoproliferative disease that is often fatal (59, 61, 65, 83). HTLV-1-infected leukemic lymphocytes exhibit deregulated cell cycle progression and characteristic multinucleation or polyploidy (evidenced by the appearance of flower-shaped or lobulated nuclei). A conserved sequence, known as pX, located within the 3′ terminus of the HTLV-1 genome, encodes at least five nonstructural regulatory factors, including the viral transactivator Tax and an alternative splice-variant, p30II (or Tax open reading frame II [ORF II], Tof), which was shown to possess a functional transactivation domain (6, 13, 15, 29, 34, 35, 66, 86, 87). The pX sequence is generally retained in the majority of ATLL patient isolates, even those containing partially deleted proviruses (33, 68), indicative of its importance for pathogenesis. The viral Tax protein transcriptionally activates numerous lymphoproliferative pathways (NF-κB, CREB/ATF, and p67SRF) (29, 72, 73, 74, 75, 80, 84, 88) and has been shown to inhibit transcription functions associated with the tumor suppressor p53, which likely contributes to a loss of G1/S-phase checkpoint control in HTLV-1-infected T cells (8, 46, 58). Many of the pleiotropic effects of Tax upon cellular signaling may derive from its aberrant recruitment of the transcriptional coactivators, p300/CREB-binding protein (p300/CBP) and p300/CBP-associated factor (P/CAF) (9, 22, 23, 27, 36, 37, 49, 50, 77, 78). Further, Tax interacts with cell cycle modulators, including D-type cylin-cdk4/6 complexes, retinoblastoma (Rb) protein, and the human mitotic arrest deficiency type 1 (hMAD-1) protein (21, 28, 31, 32, 39, 47, 52, 76). Although HTLV-1 Tax expression markedly promotes G1/S transition (38, 40, 64), Tax has been demonstrated to inhibit Myc-dependent transactivation and prevent Myc-associated anchorage-independent cell growth (67). As ATLL patient-derived lymphocytes and tumors from HTLV-1 pX transgenic mice are known to possess deregulated Myc functions, these findings collectively suggest that other pX-encoded factors may influence Myc to promote cellular transformation by HTLV-1 (20, 43, 63). The Myc transcription factor promotes S-phase cell cycle entry, induces apoptosis or programmed cell death, and causes neoplastic cellular transformation (2, 3, 7, 12, 19, 41, 51). The expression of the Myc protooncogene is deregulated in many solid tumors and hematological malignancies, including ATLL, diffuse large-cell lymphomas, CD30+ anaplastic large-cell lymphomas, and Burkitt's B-cell lymphomas (18, 24, 26, 43, 55, 60). The transforming viruses, HTLV-1 and Epstein Barr virus, deregulate Myc functions associated with development of ATLL and Burkitt's lymphomas, respectively (11, 18, 26, 43, 63, 67). Our preliminary studies indicated that the HTLV-1 accessory protein p30II markedly increases S-phase cell cycle progression and induces significant polyploidy. As relatively little is known with respect to the roles of pX-encoded factors (e.g., p30II, p13II, p12I, and Rexp27) in HTLV-1-associated pathogenesis (6, 29, 34, 35), we sought to characterize the molecular mechanism by which p30II promotes Myc-dependent S-phase progression and multinucleation. While others have proposed that p30II's transcriptional functions are targeted against the viral LTR to repress HTLV-1 gene expression (1, 86, 87), the physiological role of p30II in ATLL-development remains unclear. Using microarray analyses, we now demonstrate that numerous cellular genes are transcriptionally activated by HTLV-1 p30II in a 60-kDa Tat-interacting protein (TIP60)-dependent or TIP60-independent manner. Nicot et al. (48) and Younis et al. (85) have shown that p30II binds and inhibits nuclear export of the doubly spliced Tax/Rex HTLV-1 mRNA, and it is intriguing that p30II might perform diverse functions to regulate viral gene expression and promote altered cellular growth, as has been noted for Tax, which drives LTR transactivation and deregulates host lymphoproliferative-signaling pathways (13, 21, 28, 29, 38, 40, 47, 52, 64, 72-76, 84). Robek et al. (62) have previously demonstrated that p30II is dispensable for immortalization and transformation of human peripheral blood mononuclear cells by an infectious HTLV-1 molecular clone, ACH.p30II, which is defective for p30II production; however, the ACH.p30II mutant exhibited an approximately 20 to 50% reduction in transformation efficiency compared to the wild-type ACH.wt (62), suggesting that p30II is required for the full transforming potential of HTLV-1. Importantly, our findings indicate that HTLV-1 p30II is a novel retroviral modulator of Myc transcriptional and of transforming activities that may significantly contribute to adult T-cell leukemogenesis through stabilization of Myc-TIP60 transcriptional interactions.

Flow cytometry (FCM) is a fluorescence‐based single‐cell experimental technology that is routinely applied in biomedical research for identifying cellular biomarkers of normal physiological responses and abnormal disease states. While many computational methods have been developed that focus on identifying cell populations in individual FCM samples, very few have addressed how the identified cell populations can be matched across samples for comparative analysis. This article presents FlowMap‐FR, a novel method for cell population mapping across FCM samples. FlowMap‐FR is based on the Friedman–Rafsky nonparametric test statistic (FR statistic), which quantifies the equivalence of multivariate distributions. As applied to FCM data by FlowMap‐FR, the FR statistic objectively quantifies the similarity between cell populations based on the shapes, sizes, and positions of fluorescence data distributions in the multidimensional feature space. To test and evaluate the performance of FlowMap‐FR, we simulated the kinds of biological and technical sample variations that are commonly observed in FCM data. The results show that FlowMap‐FR is able to effectively identify equivalent cell populations between samples under scenarios of proportion differences and modest position shifts. As a statistical test, FlowMap‐FR can be used to determine whether the expression of a cellular marker is statistically different between two cell populations, suggesting candidates for new cellular phenotypes by providing an objective statistical measure. In addition, FlowMap‐FR can indicate situations in which inappropriate splitting or merging of cell populations has occurred during gating procedures. We compared the FR statistic with the symmetric version of Kullback–Leibler divergence measure used in a previous population matching method with both simulated and real data. The FR statistic outperforms the symmetric version of KL‐distance in distinguishing equivalent from nonequivalent cell populations. FlowMap‐FR was also employed as a distance metric to match cell populations delineated by manual gating across 30 FCM samples from a benchmark FlowCAP data set. An F‐measure of 0.88 was obtained, indicating high precision and recall of the FR‐based population matching results. FlowMap‐FR has been implemented as a standalone R/Bioconductor package so that it can be easily incorporated into current FCM data analytical workflows. © 2015 International Society for Advancement of Cytometry

The back cover of Gene Expression Studies Using Affymetrix Microarrays (hereafter known as GESUAM) states that the text “tears down the omnipresent language barriers among molecular biology, bioinf...

Background —Moderate alcohol intake is associated with lower atherosclerosis risk, presumably due to increased HDL cholesterol (HDL-C) concentrations; however, the metabolic mechanisms of this increase are poorly understood. Methods and Results —We tested the hypothesis that ethanol increases HDL-C by raising transport rates (TRs) of the major HDL apolipoproteins apoA-I and -II. We measured the turnover of these apolipoproteins in vivo in paired studies with and without alcohol consumption in 14 subjects. The fractional catabolic rate (FCR) and TR of radiolabeled apoA-I and -II were determined in the last 2 weeks of a 4-week Western-type metabolic diet, without (control) or with alcohol in isocaloric exchange for carbohydrates. Alcohol was given as vodka in fixed amounts ranging from 0.20 to 0.81 g · kg −1 · d −1 (mean±SD 0.45±0.19) to reflect the usual daily intake of each subject. HDL-C concentrations increased 18% with alcohol compared with the control (Wilcoxon matched-pairs test, P =0.002). The apoA-I concentrations increased by 10% ( P =0.048) and apoA-II concentrations increased by 17% ( P =0.005) due to higher apoA-I and -II TRs, respectively, whereas the FCR of both apoA-I and -II did not change. The amount of alcohol consumed correlated with the degree of increase in HDL-C (Pearson’s r =0.66, P =0.01) and apoA-I TR ( r =0.57, P =0.03). The increase in HDL-C also correlated with the increase in apoA-I TR ( r =0.61, P =0.02). Conclusions —Alcohol intake increases HDL-C in a dose-dependent fashion, associated with and possibly caused by an increase in the TR of HDL apolipoproteins apoA-I and -II.

To assess the association of zona pellucida micromanipulation and subsequent development of monozygotic twins, cases of assisted embryo hatching (AH) and intracytoplasmic sperm injection (ICSI) were identified and related to treatment type, implantation and zygosity data. Embryology records from all patients undergoing in-vitro fertilization (IVF) at this centre from January 1995 to March 1998 were reviewed. In this study, 3546 transfer cycles were completed, with clinical pregnancy established in 1911 (54% per transfer) patients undergoing a single IVF cycle. These pregnancies occurred in 1674 (88%) IVF cycles, 120 (6%) donor oocyte cycles (DER), and 117 (6%) frozen embryo transfer (FET) cycles. During the study period, 23 cases of monozygotic (MZ) twins were identified, representing an overall frequency of 1.2%. Chorionicity was determined by transvaginal ultrasound at 7 weeks when the number of embryos transferred was less than the number of fetal heart-beats, or when >1 fetal heartbeat per gestational sac was seen. Zygosity was confirmed by placental evaluation at delivery, and corroborated the antenatal diagnosis in all cases. Among IVF study patients the frequency of MZ twinning was not statistically different between zona manipulated and zona intact subgroups. While this investigation is the largest to date describing the relationship between MZ twins and zona procedures, studies with even greater statistical power are needed to clarify it more precisely, particularly in DER and FET settings. A greater overall frequency of MZ twinning for IVF patients may be a function of the higher number of embryos transferred in IVF, rather than discrete zona manipulations.

A possible relationship between change in dietary cholesterol absorptionand plasma lipoprotein responsiveness was examined in 18 normal subjects fed lowfat low cholesterol, high fat low cholesterol, and high fat high cholesteroldiets. For the group, neither dietary cholesterol nor dietary fat affected thepercentage dietary cholesterol absorption, whreas dietary cholesterol intakeraised total and LDL-C and dietary fat raised total, LDL, and HDL-C. On a fixeddiet there was approximately a 2-fold variation among subjects in percentagedietary cholesterol absorption. Subjects also varied in response to dietarycholesterol and fat with regard to dietary cholesterol absorption and plasmalipoprotein responsiveness. There was a U-shaped parabolic relationship betweendietary cholesterol-induced percent change in LDL-C and the change in percentagedietary cholesterol absorption (R2 = 0.62,P = 0.005). A similar but weaker relationship characterizedthe responsiveness of HDL-C (R2 = 0.38,P = 0.05). For the group, increased cholesterol intakeraised dietary cholesterol mass absorption from 1.6 to 4.6 mg/kg per day, butthe range of increase was from 1 to 4.7 mg/kg per day. Increased fat intake alsoaffected dietary cholesterol mass absorption with most subjects displaying astrong inverse relationship between fat intake and mass absorption(r = −0.77, P < 0.003). Insummary: i) the percentage change in dietary cholesterolabsorption in response to dietary cholesterol does appear to regulate dietresponsiveness of LDL and HDL-C, and ii) the large variabilityin percent absorption and changes in percentage and mass absorption in responseto dietary cholesterol suggest the presence of genetically determineddifferences among individuals in the regulation of dietary cholesterolabsorption.—Sehayek, E., C. Nath, T. Heinemann, M. McGee, C. E. Seidman, P.Samuel, and J. L. Breslow. U-shape relationship between change in dietarycholesterol absorption and plasma lipoprotein responsiveness and evidence forextreme interindividual variation in dietary cholesterol absorption in humans.J. Lipid Res. 1998. 39: 2415–2422.

A test for categorical time series is developed which is based on Fisher’s test for continuous-parameter time series. Instead of using a test based on the Fourier periodog ram for spectral analysis, we utilize the Walsh–Fourier periodogram for testing purposes. We briefly explain the theory behind Walsh–Fourier analysis and some of its recent applications. Asymptotic results for the distribution of the new test statistic for Walsh–Fourier spectra are presented and compared with a simulated distribution. We also perform power studies in order to assess the detection capability of the test. In the presence of multiple peaks in the spectrum, this test tends to lose power. Therefore, we also explore several alternatives to the test for Walsh–Fourier spectra and apply all of the alternative methods to a realization of geomagnetic reversals

Cellular and humoral immunity have been implicated in the pathogenesis of atherosclerosis. To determine whether an intact immune system is necessary for the formation of atherosclerotic lesions, we have generated immunodeficient mice with hypercholesterolemia and atherosclerosis by crossbreeding the apolipoprotein E (apoE)-deficient mouse with the recombinase activating gene 1 ( Rag-1 ) knockout mouse. Chow-fed immunodeficient mice with targeted disruption in both apoE and Rag-1 (E0/R0) had a 2-fold decrement in aortic root lesion size at 16 weeks of age, compared with immunocompetent littermates, which were heterozygotes at the Rag-1 locus (E0/R1). Nearly all atherosclerotic lesions from chow-fed animals were limited to raised foam cell fatty streaks. In contrast, when a second group of animals was fed a high-fat Western-type diet to accelerate lesion development, there were no differences in either aortic root lesion size or the percent of the total aorta occupied by lesions. Fibrous plaques with well-defined caps and necrotic cores were detected in both Western diet-fed E0/R0 and E0/R1 animals. We conclude that T and B lymphocytes play only a minor role in the rate of forming foam cell lesions, and they are not necessary for the formation of fibroproliferative plaques.

The Virus Pathogen Resource (ViPR; www.viprbrc.org) and Influenza Research Database (IRD; www.fludb.org) have developed a metadata-driven Comparative Analysis Tool for Sequences (meta-CATS), which performs statistical comparative analyses of nucleotide and amino acid sequence data to identify correlations between sequence variations and virus attributes (metadata). Meta-CATS guides users through: selecting a set of nucleotide or protein sequences; dividing them into multiple groups based on any associated metadata attribute (e.g. isolation location, host species); performing a statistical test at each aligned position; and identifying all residues that significantly differ between the groups. As proofs of concept, we have used meta-CATS to identify sequence biomarkers associated with dengue viruses isolated from different hemispheres, and to identify variations in the NS1 protein that are unique to each of the 4 dengue serotypes. Meta-CATS is made freely available to virology researchers to identify genotype-phenotype correlations for development of improved vaccines, diagnostics, and therapeutics.

Genetic drift of influenza virus genomic sequences occurs through the combined effects of sequence alterations introduced by a low-fidelity polymerase and the varying selective pressures experienced as the virus migrates through different host environments. While traditional phylogenetic analysis is useful in tracking the evolutionary heritage of these viruses, the specific genetic determinants that dictate important phenotypic characteristics are often difficult to discern within the complex genetic background arising through evolution. Here we describe a novel influenza virus sequence feature variant type (Flu-SFVT) approach, made available through the public Influenza Research Database resource ( www.fludb.org ), in which variant types (VTs) identified in defined influenza virus protein sequence features (SFs) are used for genotype-phenotype association studies. Since SFs have been defined for all influenza virus proteins based on known structural, functional, and immune epitope recognition properties, the Flu-SFVT approach allows the rapid identification of the molecular genetic determinants of important influenza virus characteristics and their connection to underlying biological functions. We demonstrate the use of the SFVT approach to obtain statistical evidence for effects of NS1 protein sequence variations in dictating influenza virus host range restriction.

Background In microarray experiments with small sample sizes, it is a challenge to estimate p-values accurately and decide cutoff p-values for gene selection appropriately. Although permutation-based methods have proved to have greater sensitivity and specificity than the regular t-test, their p-values are highly discrete due to the limited number of permutations available in very small sample sizes. Furthermore, estimated permutation-based p-values for true nulls are highly correlated and not uniformly distributed between zero and one, making it difficult to use current false discovery rate (FDR)-controlling methods. Results We propose a model-based information sharing method (MBIS) that, after an appropriate data transformation, utilizes information shared among genes. We use a normal distribution to model the mean differences of true nulls across two experimental conditions. The parameters of the model are then estimated using all data in hand. Based on this model, p-values, which are uniformly distributed from true nulls, are calculated. Then, since FDR-controlling methods are generally not well suited to microarray data with very small sample sizes, we select genes for a given cutoff p-value and then estimate the false discovery rate. Conclusion Simulation studies and analysis using real microarray data show that the proposed method, MBIS, is more powerful and reliable than current methods. It has wide application to a variety of situations.

Motivation: As next generation sequencing is rapidly adding new genomes, their correct placement in the taxonomy needs verification. However, the current methods for confirming classification of a taxon or suggesting revision for a potential misplacement relies on computationally intense multi-sequence alignment followed by an iterative adjustment of the distance matrix. Due to intra-heterogeneity issues with the 16S rRNA marker, no classifier is available for sub-genus level, which could readily suggest a classification for a novel 16S rRNA sequence. Metagenomics further complicates the issue by generating fragmented 16S rRNA sequences. This article proposes a novel alignment-free method for representing the microbial profiles using extensible Markov models (EMMs) with an extended Karlin–Altschul statistical framework similar to the classic alignment paradigm. We propose a log odds (LODs) score classifier based on Gumbel difference distribution that confirms correct classifications with statistical significance qualifications and suggests revisions where necessary. Results: We tested our method by generating a sub-genus level classifier with which we re-evaluated classifications of 676 microbial organisms using the NCBI FTP database for the 16S rRNA. The results confirm current classification for all genera while ascertaining significance at 95%. Furthermore, this novel classifier isolates heterogeneity issues to a mere 12 strains while confirming classifications with significance qualification for the remaining 98%. The models require less memory than that needed by multi-sequence alignments and have better time complexity than the current methods. The classifier operates at sub-genus level, and thus outperforms the naive Bayes classifier of the RNA Database Project where much of the taxonomic analysis is available online. Finally, using information redundancy in model building, we show that the method applies to metagenomic fragment classification of 19 Escherichia coli strains. Availability and implementation: Source code and binaries freely available for download at http://lyle.smu.edu/IDA/EMMSA/, implemented in JAVA and supported on MS Windows. Contact: mallik@kotamarti.com; mhd@lyle.smu.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Introduction Affymetrix GeneChip® high-density oligonucleotide arrays are widely used in biological and medical research because of production reproducibility, which facilitates the comparison of results between experiment runs. In order to obtain high-level classification and cluster analysis that can be trusted, it is important to perform various pre-processing steps on the probe-level data to control for variability in sample processing and array hybridization. Many proposed preprocessing methods are parametric, in that they assume that the background noise generated by microarray data is a random sample from a statistical distribution, typically a normal distribution. The quality of the final results depends on the validity of such assumptions. Results We propose a Distribution Free Convolution Model (DFCM) to circumvent observed deficiencies in meeting and validating distribution assumptions of parametric methods. Knowledge of array structure and the biological function of the probes indicate that the intensities of mismatched (MM) probes that correspond to the smallest perfect match (PM) intensities can be used to estimate the background noise. Specifically, we obtain the smallest q2 percent of the MM intensities that are associated with the lowest q1 percent PM intensities, and use these intensities to estimate background. Conclusion Using the Affymetrix Latin Square spike-in experiments, we show that the background noise generated by microarray experiments typically is not well modeled by a single overall normal distribution. We further show that the signal is not exponentially distributed, as is also commonly assumed. Therefore, DFCM has better sensitivity and specificity, as measured by ROC curves and area under the curve (AUC) than MAS 5.0, RMA, RMA with no background correction (RMA-noBG), GCRMA, PLIER, and dChip (MBEI) for preprocessing of Affymetrix microarray data. These results hold for two spike-in data sets and one real data set that were analyzed. Comparisons with other methods on two spike-in data sets and one real data set show that our nonparametric methods are a superior alternative for background correction of Affymetrix data.

We present a new DNA/RNA sequence visualization technique, Temporal Chaos Game Representation (TCGR), which is an extension of Frequency Chaos Game Representation (FCGR). Unlike earlier CGR variants, TCGR illustrates the distribution of nucleotide sub-patterns at different positions within a sequence, and it can be applied to sets of sequences as well as individual sequences. TCGRs are suitable for short or long sequences. Preliminary experiments examining patterns of nucleotide occurrences in micro-RNA data illustrate not only the informative nature of the images, but clearly indicate the variability of distributions based on position, and the similarity and differences of distributions across various species.

Despite the growing number of studies of imagery and the use of complementary and alternative modalities as treatments for asthma, research on mental imagery in adults with asthma is practically, nonexistent. The purpose of this feasibility study was to lay groundwork for a larger follow-up clinical trial.To determine whether pulmonary function, asthma symptoms, quality of life, depression, anxiety, and power differ over time in adults with asthma who do and do not practice mental imagery (MI). (Power is the ability to make aware choices with the intention of freely involving oneself in creating desired change.)Randomized controlled study using univariate repeated measures analysis of variance (ANOVA) and replacement through block design.Lenox Hill Hospital, an affiliate of New York University Medical School, New York, NY.Sixty-eight adults with symptomatic asthma, after 4 weeks of baseline data collection and analysis, met requirements for this randomized controlled study. Thirty-three completed pulmonary function as well as self-report tests at 4 time points over 17 weeks. The 16 experimental participants also completed the 4-session imagery protocol.Individual imagery instruction (week 1) and follow-up (weeks 4, 9, 15). Participants were given 7 imagery exercises to select from and practice 3 times a day for a total of 15 minutes.1) Spirometry (FEV1); 2) medication use; 3) Asthma Quality of Life Questionnaire; 4) Beck Depression Inventory; 5) Spielberger Anxiety Scales (A-State and A-Trait); 6) Barrett Power as Knowing Participation in Change Tool, Version II; 7) Epstein Balloon Test of Ability to Image.There was little evidence of statistical change in this feasibility study; yet, valuable lessons were learned. Paired t-tests indicated there was a significant difference in the total power scores in the imagery group, and in the expected direction (two-tailed, t-statistic = -2.3, P = 0.035) and the choices sub-scale (two-tailed, tstatistic = -2.93, P = 0.01) of the power instrument from weeks one to 16 of the study. Eight of 17 (47%) participants in the MI group reduced or discontinued their medications. Three of 16 (19%) participants in the control group reduced their medications; none discontinued. Chi-square indicated differences between groups (X2 = 4.66, P = 0.05). Persons who reduced or discontinued their medications showed neither an increase in pulmonary function prior to medication discontinuation, nor a fall in these parameters following discontinuation.Findings related to major outcome measures must be viewed with caution due to the small sample size resulting from attrition related to labor intensiveness and, therefore, low statistical power. However, the study did provide significant data to plan a larger scale study of the use of mental imagery with adult asthmatics. The study also demonstrated that imagery is inexpensive, safe and, with training, can be used as an adjunct therapy by patients themselves. Its efficacy needs additional exploration. Further research for adults with asthma who practice imagery is important, as current treatments are not entirely efficacious. Lessons learned in this study may facilitate improvement in research designs.

It is proposed that the pruritus of cholestasis is, in part, centrally mediated by endogenous opioid peptides. The expression of these peptides and their receptors on neurons displays a circadian rhythm, as does the scratching activity in patients with cholestasis and pruritus. Because light has regulatory effects on circadian rhythms via retinothalamic pathways, we hypothesized that bright-light therapy (BLT) reflected toward the eyes might alter the pruritus of cholestasis. To test this hypothesis, we studied the effect of BLT on this form of pruritus.Eight patients with chronic liver disease of different etiologies and pruritus were studied in an open-label, pilot study of 8-wk duration. BLT (10,000 lux) was administered for up to 60 min twice a day. Pruritus was assessed subjectively by a visual analog scale from which a visual analog score (VAS) was derived, and objectively, by a scratching activity monitoring system that recorded hourly scratching activity (HSA).In seven of the eight patients studied, the mean HSA was lower during BLT. BLT was associated with a mean decrease in HSA of 32.2% (p = 0.123). The mean VAS for pruritus was lower in six patients during BLT; the mean VAS score derived from the eight patients studied decreased by 42% (p = 0.05) during treatment.The results of this short-term study suggest that the pruritus of cholestasis is responsive to bright light reflected toward the eyes and that in some patients, BLT may ameliorate this form of pruritus.

The commercial availability of highly purified, s.c. administered urinary follicle stimulating hormone (FSH) preparations for ovarian stimulation marked the beginning of a new era in the treatment of infertility. As these new formulations contain essentially no luteinizing hormone (LH), supplemental LH may be needed for optimal folliculogenesis. It was the aim of this pilot study to compare fertilization rates, embryo morphology, implantation rates and pregnancy outcomes prospectively in two age-matched patient groups: women who received highly purified FSH (FSH-HP) (n = 17), and women who received FSH-HP plus recombinant human LH (rhLH, n = 14) throughout ovarian stimulation. All patients received mid-luteal pituitary down-regulation with s.c. gonadotrophin-releasing hormone agonist (GnRHa) (leuprolide). Mean implantation rates were 26.9 and 11.9% in the FSH-HP only and FSH-HP + rhLH groups respectively. The mean clinical pregnancy/initiated cycle rate was 64.7 and 35.7% for the FSH-HP only and FSH-HP + rhLH patients respectively. FSH-HP patients and FSH-HP + rhLH patients achieved clinical pregnancy/transfer rates of 68.8 and 45.5% respectively. One patient in the FSH-HP + rhLH group had a spontaneous abortion; no pregnancy losses occurred in the FSH-HP only group. There were more cancellations for poor ovarian response among FSH-HP + rhLH patients (n = 3) than among FSH-HP patients (n = 1). The trend toward better pregnancy outcomes among patients who received FSH-HP without supplemental rhLH did not reach statistical significance. It is postulated that appropriate endogenous LH concentrations exist despite luteal GnRHa pituitary suppression, thereby obviating the need for supplemental LH administration.

Objective: To describe nationwide practice trends for two principal techniques of abdominal hysterectomy in the United States, numbers and rates of total (TAH) and supracervical (SCH) hysterectomy were reviewed with charges for each operation. Methods: Practice patterns for all inpatient TAH and SCH discharges in the US from 1991 to 1994 were studied using HCUP-3 NIS, a nationwide hospital discharge database. Hysterectomies performed for malignant disease, vaginally or with laparoscopic assistance were not sampled. For each year studied, the number and rate of TAH and SCH, average length of stay (LOS), and mean institutional charge were evaluated. Results: From 1991 to 1994, the US TAH rate (cases/10 000 females) decreased significantly from 25.7 to 20.5 (P = 0.02). During the same interval the SCH rate increased significantly from 0.16 to 0.41 (P = 0.04). Nevertheless, TAH accounted for >99% of all abdominal hysterectomies for each of the 4 years evaluated. The mean institutional charges for the two operations generally depicted SCH to be more costly than TAH. Conclusion: The national rates of TAH and SCH rates changed significantly in the United States from 1991 to 1994, with TAH declining and SCH increasing. This mix of cases continues to reflect a strong preference for TAH. Although hospital charges for both procedures increased during this study, these data show that SCH is more expensive than TAH. The much lower utilization of SCH renders nominal its impact on national healthcare expenditures, however. Further studies are needed to assess specific causative factors for these changes in US hysterectomy technique.

To describe practice trends for total abdominal hysterectomy (TAH) and supracervical abdominal hysterectomy (SCH) in New York State and to identify fiscal features associated with these two operations, all inpatient discharges for TAH and SCH performed for benign indications from 1990 to 1996 were reviewed using the Statewide Planning and Resource Cooperative System, a centralized data reporting system. For each year examined, the number of TAHs and SCHs performed, the procedure rates adjusted for the total New York State female population, and the per diem charge (calculated from mean institutional charge as a function of average length of stay) were evaluated. While the TAH rate declined in New York State, from 34.0 in 1990 to 28.4 in 1996 (P = .01), the SCH rate increased nearly five-fold during the same period, from 0.62 to 3.07 (P = .0003). Patients tended to be discharged later following SCH than for TAH, although by 1996, the LOS for both operations was equivalent. The per diem institutional charge for SCH was consistently higher than for TAH in each year studied. The changes in charge and relative frequency of TAH and SCH in New York State invite further study to describe these trends more fully.

Gene expression microarrays are widely used to study genome-wide gene expression profiles. Many microarray analysis methods are available, making it challenging to decide which method to use. While the effectiveness of some of these methods has been assessed using artificial spike-in data sets, analytical approaches that work well with spike-in data may not work as well with data from real biological samples. To evaluate these methods we applied Gene Ontology (GO) term co-clustering as a comparative tool to evaluate 300 different data processing pipelines composed of various background correction, normalization and summarization methods using real biological data, based on the premise that an improvement in any step of microarray data analysis should be reflected in improved co-clustering of related genes. Our results suggest that background correction has little affect on GO term co-clustering characteristics, normalization has a big impact, some summarization methods constantly outperform others, some interdependencies exist among these methods, e.g., a good normalization method may work well with one summarization method but not another. An automated method for running and assessing these 300 pipelines has been made available through the Immunology Database and Analysis Portal (ImmPort; www.immport.org) - a public database resource funded by NIAID to support the management and analysis of clinical and mechanistic data generated by their funded investigators.

We propose a new method based on probe-level data (PLIDEG) to filter differentially expressed genes from non-differentially expressed genes. We compare this new method with others based on expression values by using two spikein data sets. With the extra information provided by probe level data, PLIDEG not only controls type I error, but also increases the power of detecting DEGs, simultaneously. Therefore, PLIDEG can efficiently separate DEGs and non-DEGs without requiring the estimation of the number of non-DEGs. Based on theoretical analysis and results from application to real microarray data, we confirm these good features of this new method.