Statistical Science

Genome databases continue to expand with no change in the basic format of sequence data. The prevalent use of the Classic alignment based search tools like BLAST have significantly pushed the limits of Genome Isolate research. The relatively new frontier of Metagenomic research deals with thousands of diverse genomes with newer demands beyond the current homologue search and analysis. Compressing sequence data into a complex form could facilitate a broader range of sequence analyses. To this end, this research explores reorganizing sequence data as complex Markov signatures also known as Extensible Markov Models. Markov models have found successful application in Biological Sequence analysis applications through small, but important extensions to the original theory of Markov Chains. Extensible Markov Model (EMM) offers a novel Quasi-alignment complement to the classic alignment based homologous sequence search methods like BLAST. EMM based BioInformatic analysis (EMMBA) incorporates automatic learning which allows the Markov chain creation dynamically. Oligonucletide or Genomic word frequencies form the core sequence data in alignment free methods. EMMBA extends the Karlin-Altschul statistics to bring forth an analogous E-Score statistical significance to the Quasi-alignment domain. By consolidating a community of sequences into a single searchable profile, EMM methodology further reduces the search space for classification. Through dynamic generation of the score matrix for each community profile, EMMBA fine tunes the score assignments. Each evaluation iteratively adjusts the profile score matrix to account for point probabilities of the query to ensure Karlin-Altschul assumptions are satisfied to derive meaningful statistical significance. The presence of multiple Quasi-alignments resembles multiple local alignments of BLAST. Quasi-alignments are scored based on a difference distribution of Gumbel scores. Species signature profiles allow for statistical validation of novel species identification. Working in EMM transformation space speeds up

Motivation: Affymetrix GeneChip arrays require summarization in order to combine the probe-level intensities into one value representing the expression level of a gene. However, probe intensity measurements are expected to be affected by different levels of non-specific- and cross-hybridization to non-specific transcripts. Here, we present a new summarization technique, the Distribution Free Weighted method (DFW), which uses information about the variability in probe behavior to estimate the extent of non-specific and cross-hybridization for each probe. The contribution of the probe is weighted accordingly during summarization, without making any distributional assumptions for the probe-level data.Results: We compare DFW with several popular summarization methods on spike-in datasets, via both our own calculations and the ‘Affycomp II’ competition. The results show that DFW outperforms other methods when sensitivity and specificity are considered simultaneously. With the Affycomp sp...

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...

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 ...

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 tes...

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.

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.

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 HCUP3 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/l0 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

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. Fibr...

The Ontology for Biomedical Investigations (OBI) is an ontology that provides terms with precisely defined meanings to describe all aspects of how investigations in the biological and medical domains are conducted. OBI re-uses ontologies that provide a representation of biomedical knowledge from the Open Biological and Biomedical Ontologies (OBO) project and adds the ability to describe how this knowledge was derived. We here describe the state of OBI and several applications that are using it, such as adding semantic expressivity to existing databases, building data entry forms, and enabling interoperability between knowledge resources. OBI covers all phases of the investigation process, such as planning, execution and reporting. It represents information and material entities that participate in

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. METHODS: 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). RESULTS: 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 ϭ 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 ϭ 0.05) during treatment. CONCLUSIONS: 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 Affymetrix HGU-133A spike in data set has been used for determining the sensitivity and specificity of various methods for the analysis of microarray data. We show that there are 22 additional probe sets that detect spike in RNAs that should be considered as spike in probe sets. We assign each proposed spiked-in probe set to a concentration group within the Latin Square design, and examine the effects of the additional spiked-in probe sets on assessing the accuracy of analysis methods currently in use. We show that several popular preprocessing methods are more sensitive and specific when the new spike-ins are used to determine false positive and false negative rates.

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...

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. Thir...

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 resear...

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 FlowMa...