Exact P-value Research Articles

Treponema denticola associates with increased levels of MMP‐8 and MMP‐9 in gingival crevicular fluid

The aim was to assess the association between the presence of site-specific subgingival micro-organisms and the levels of matrix metalloproteinases-8 and matrix metalloproteinases-9 (MMP-8 and MMP-9) in gingival crevicular fluid (GCF). The patient group consisted of 56 subjects with periodontitis and the control group of 43 subjects without periodontitis. GCF samples from four test sites for each subject were collected. Polymerase chain reaction was used to detect the presence of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia, and Treponema denticola. MMP-8 concentrations were analyzed by a time-resolved immunofluorometric assay, and MMP-9 levels were determined by enzyme-linked immunosorbent assay. Student's unpaired t-test, chi-square test, and Fisher's exact P-value were calculated. The presence of T.denticola in the test sites was significantly higher in the patient group than in the control group. The presence of T.forsythia and T.denticola was associated with increased levels of MMP-8 in the test sites. Respectively, site-specific presence of T.denticola was associated with an increase in MMP-9 levels in three of the four test sites. The presence of subgingival micro-organisms in GCF, particularly T.denticola, appeared to induce a host response with an increased release of MMP-8 and MMP-9 in the test sites.

The Influence of Social Desirability on Self-Reported Sexual Behavior in HIV Survey in Rural Ethiopia

Objective: It is in order to examine associations between social desirability (SD) and self-reports of abstinence among youths in rural Ethiopia. Methods: Youths of ages 15 - 24 (114 participants) were administered questionnaire to assess HIV knowledge and primary abstinence and a modified Marlowe-Crowne Social Desirability Scale to assess SD bias. The relationships between SD groups (dichotomized into high and low) and abstinence by various characteristics were assessed by using Fisher’s exact p-values. Results: The odds of individuals reporting abstinence were 13.2 times greater in the high SD group compared to the low SD group (p-value 0.002) when adjusted for education, gender, age group, and HIV knowledge. The differences in abstinence between the high and low SD score groups were also examined for selected variables. Conclusions: Individuals who exhibited more SD bias were more likely to report primary abstinence. SD bias should be considered when conducting self-reported surveys to measure the effectiveness of HIV prevention programs.

On the meaning of the likelihood ratio: Is a large number always an indication of strength of evidence?

There is general lack of awareness that high LR based on complex propositions e.g. three contributors, does not necessarily translate into probative evidence against a suspect. In some cases there is an increased chance of false inclusion of a person of interest. This is an issue for all LR-based models. One way to address this issue is to further evaluate or qualify the estimated LR by a performance test. Based on simulations, this was achieved by non-contributor-testing: replacing the reference profile of interest (typically the suspect's profile), by the profile of a simulated random man. An exact p-value can also be calculated, giving the chance of observing an LR-value exceeding the estimated if the defense hypothesis is true.

The mid p-value in exact tests for Hardy-Weinberg equilibrium

Exact tests for Hardy-Weinberg equilibrium are widely used in genetic association studies. We evaluate the mid p-value, unknown in the genetics literature, as an alternative for the standard p-value in the exact test. The type 1 error rate and the power of the exact test are calculated for different sample sizes, significance levels, minor allele counts and degrees of deviation from equilibrium. Three different p-value are considered: the standard two-sided p-value, the doubled one-sided p-value and the mid p-value. Practical implications of using the mid p-value are discussed with HapMap datasets and a data set on colon cancer. The mid p-value is shown to have a type 1 error rate that is always closer to the nominal level, and to have better power. Differences between the standard p-value and the mid p-value can be large for insignificant results, and are smaller for significant results. The analysis of empirical databases shows that the mid p-value uncovers more significant markers, and that the equilibrium null distribution is not tenable for both databases. The standard exact p-value is overly conservative, in particular for small minor allele frequencies. The mid p-value ameliorates this problem by bringing the rejection rate closer to the nominal level, at the price of occasionally exceeding the nominal level.

G6PD Deficient Variants Differ in Risk of Hospitalization Among Gaza Strip Palestinian Children

AbstractAbstract 4268Glucose-6-phosphate dehydrogenase (G6PD) deficiency, affecting more than 500 million people worldwide, is one of the most common inherited disorders. There are 186 G6PD mutations published, with some that cluster within defined ethnic/racial groups, and in some populations more than one variant is encountered. These prevalent variants are generally considered to be benign in adults, but their morbidity, presenting as acute hemolytic anemia, in young children can be significant. However, comprehensive molecular characterization of ethnically prevalent G6PD mutants and their relative clinical significance is lacking.In a region where the frequency of G6PD deficiency in the population is significant (>3%) and fava beans, green and dried, are a dietary staple, the risk of acute hemolytic crisis is significant. We studied 80 consecutively hospitalized unrelated Gaza Strip Palestinian children (ages 34–52 months, mean=39.5) for acute hemolytic anemia and found G6PD deficiency accounted for most cases (65 of 80 children; 81%) and almost all occurred after ingestion of green fava beans. Molecular analyses revealed 5 separate mutations, with 3 accounting for most cases. These were G6PD Mediterraneanc.563T, African G6PD A-c.202A/c.376G, and G6PD Cairoc.404C with relative allele frequencies of 0.33, 0.26, and 0.18 respectively. The detection of G6PD Cairo in 14 unrelated hospitalized children was surprising as this variant was encountered previously only in a single Egyptian individual. This unanticipated molecular heterogeneity of G6PD variants among Gaza Strip Palestinians provided a unique opportunity to test their relative clinical significance. We compared the prevalence of these variants to a control group consisting of 466 self-reported healthy, non-anemic, unrelated Palestinian adults (46 women and 420 men; 512 X-chromosomes). Within this cohort, the proportion with the G6PD deficient variants was 3.3%. The most common mutation was G6PD A+c.376A (allele frequency 0.016), comprising 47% of the variants detected while the G6PD variants Mediterranean and A- had allele frequencies of 0.0098 and 0.0078, respectively, comprising 29.4% and 23.5% of the detected variants. G6PD Cairo was not detected. The proportion of G6PD Mediterranean and G6PD A- variants in the general population are equivalent to their representation in the hospitalized children population. However, the number of G6PD Cairo variants in the hospitalized cohort was vastly larger than that observed in the general population indicating that these carriers are at a greater risk of hospitalization (Table 1). We found a dramatically increased risk of acute hemolytic anemia requiring hospitalization associated with all three variants. Fisher’s Exact test was used to determine the association between the risk of hospital admission and presence of the variants and was significant for all at p<0.0001. Additionally, odds ratios for hospitalization are 41.1 (for G6PD A-) and 70.0 (for G6PD Mediterranean) compared to wild type [odds ratio was infinite for G6PD Cairo since it was not detected in the healthy population].This is the first study comparing the relative clinical impact of three prevalent G6PD deficient variants in the same population and habitat to identify clinically significant effects due to the different genetic mutations.Table 1:Distribution of G6PD variants in Gaza among hospitalized children vs. general Gaza populationG6PDMediterraneanA-Cairo+-+-+-Hospitalized children265421591466Healthy population346344620466Odds ratio (95% CI)70.0 (20.1–367.4)41.1 (13.1–168.2)∞Fisher's Exact p-value<0.0001<0.0001<0.0001Confidence interval (CI)-NSR and MMS contributed equally to this work. Disclosures:No relevant conflicts of interest to declare.

Functional Enrichment Analysis by David in Transgenic MYCN Zebrafish Model

AbstractAbstract 5114 IntroductionThe MYCN oncogene encodes a basic helix-loop-helix/leucine zipper (bHLH/LZ) transcription factor that is frequently overexpressed in hematologic malignancies neoplasms (including acute leukemia, T-cell lymphoma, and so on). MYCN acts as a poor prognostic marker to promote an aggressive phenotype. However, the mechanisms of action and pathways affected by MYCN are still largely unclear. MethodsWe induced murine MYCN gene overexpression in embryonic zebrafish through heat-shock promoter and established stable germline Tg(MYCN:HSE:EGFP) zebrafish. RNA was extracted at 3 days post fertilization from wild type (WT) and transgenic zebrafish F1 generation (TG) embryo hematopoietic cells, collected by the flow cytometer, for microarray analysis. The samples were processed and subsequently analyzed in triplicate on Zebrafish Oligo Microarrays (Agilent Technologies), containing 43, 554 sets of probe, at the Advanced Throughput Inc. The microarrays were scanned in an Agilent DNA Microarray Scanner and the images were processed using Feature Extraction software. A False Discovery Rate≤0. 05 for overall interactions effect and P<0. 001 between comparisons were used to determine differentially expressed genes (DEG). Ingenuity Pathway Analysis and DAVID performed the functional analysis of DEG. ResultsMicroarray analysis revealed 626 (342 genes up-regulated and 284 genes down-regulated) DEG that showed >2-fold change in TG comparing with that of WT. Using functional enrichment analysis by DAVID, several signaling pathways were regulated in TG samples (Table 1). MAPK signaling pathway was high activated through FGF, PDGF, BDNF and CACN high expression, promoting up-regulated of Ras and MKP, enhancing phosphorylation and leading to increase of cells proliferation. TGFβ signaling was inhibited by up-regulation of IFN Ã and Smad 6/7, which negative control of TGFβR and Smad 2/3. Further, we found that MYCN enhances the expression of skp2, via decreased p21 and increased CDK2, promoting cell cycle progression (Fig. 1). In addition, overexpression of MYCN weakened the function of mismatch repair, base excision repair, while increased apoptosis pathway mediated by p53 (up-regulated Bid gene). Meanwhile, Glycolysis/gluconeogenesis pathway was significantly up-regulated in TG fish. ConclusionsOverexpression of MYCN induced up-regulation of cell proliferation and Glycolysis/gluconeogenesis pathway (as the Warburg effect in rapidly proliferating tumors), attenuation of repair function, all of which are phenomena associated with proliferation and malignancies transformation of blood cell feature. [Display omitted] We found that MYCN down-regulates p27kip1, p57kip2 and p21cip1 through up-regulate Skp2, thus up-regulates CDK2, CycA, CycB, CycD and CycE. All above changes shortened the time taken to progress through the cell cycle. Increased MARK signaling and decreased TGFβ signaling pathways also contributed to promote cell cycle. (Red star marks the up-regulated genes).Table 1Changes in Tg(MYCN:HSE:EGFP) zebrafish hematopoietic cellssignaling pathwayregulateCount*%#P-ValueGlycolysis/Gluconeogenesis+201.20.00000037Cell cycle+423.30.00000045Tryptophan metabolism+140.80.0000086Fatty acid metabolism+130.80.0000094Cardiac muscle contraction+201.20.000038Biosynthesis of unsaturated fatty acids+90.50.000057Phenylalanine metabolism+90.50.00014Tyrosine metabolism+110.70.0004Pyruvate metabolism+110.70.001p53 signaling pathway+1310.0021Fatty acid elongation in mitochondria+60.40.0022Arginine and proline metabolism+130.80.0038Valine, leucine and isoleucine degradation+100.60.0069Alanine, aspartate and glutamate metabolism+90.50.0069Butanoate metabolism+80.50.008Mismatch repair−141.15.9E-10Homologous recombination−120.90.00000097Base excision repair−1310.0000019Spliceosome−231.80.000033Nucleotide excision repair−1310.000038Pyrimidine metabolism−191.50.000056TGFβ−81.60.00063One carbon pool by folate−60.50.0021+: up-regulated; -: down-regulated.*: genes involved in the term.#: involved genes/total genes. P-Value: the threshold of EASE Score, a modified Fisher Exact P-Value, for gene-enrichment analysis (≤0. 01). Disclosures:No relevant conflicts of interest to declare.

Prevalence of scientific misconduct among a group of researchers in Nigeria.

There is a dearth of information on the prevalence of scientific misconduct from Nigeria. This study aimed at determining the prevalence of scientific misconduct in a group of researchers in Nigeria. Factors associated with the prevalence were ascertained. A descriptive study of researchers who attended a scientific conference in 2010 was conducted using the adapted Scientific Misconduct Questionnaire-Revised (SMQ-R). Ninety-one researchers (68.9%) admitted having committed at least one of the eight listed forms of scientific misconduct. Disagreement about authorship was the most common form of misconduct committed (36.4%) while plagiarism was the least (9.2%). About 42% of researchers had committed falsification of data or plagiarism. Analysis of specific acts of misconduct showed that committing plagiarism was inversely associated with years in research (Fisher exact p-value = 0.02); falsifying data was related to perceived low effectiveness of the institution's rules and procedures for reducing scientific misconduct (X(2) = 6.44, p-value = 0.01); and succumbing to pressure from study sponsor to engage in unethical practice was related to sex of researcher (Fisher exact p-value = 0.02). The emergent data from this study is a cause for serious concern and calls for prompt intervention. The best response to reducing scientific misconduct will proceed from measures that contain both elements of prevention and enforcement. Training on research ethics has to be integrated into the curriculum of undergraduate and postgraduate students while provision should be made for in-service training of researchers. Penalties against acts of scientific misconduct should be enforced at institutional and national levels.

Regional differences among HIV patients in care: California medical monitoring project sites, 2007-2008.

Introduction:The Medical Monitoring Project (MMP) is a national, multi-site population-based supplemental HIV/AIDS surveillance project of persons receiving HIV/AIDS care. We compared California MMP data by region. Demographic characteristics, medical care experiences, HIV treatment, clinical care outcomes, and need for support services are described.Methods:HIV-infected patients 18 years or older were randomly selected from medical care facilities. In person structured interviews from 2007 - 2008 were used to assess sociodemographic characteristics, self-reported clinical outcomes, and need for supportive services. Pearson chi-squared, Fisher’s exact and Kruskal-Wallis p-values were calculated to compare regional differences.Results:Between 2007 and 2008, 899 people were interviewed: 329 (37%) in San Francisco (SF), 333 (37%) in Los Angeles (LA) and 237 (26%) in other California counties. Significant regional sociodemographic differences were found. Care received and clinical outcomes for patients in MMP were positive and few regional differences were identified. HIV case management (36%), mental health counseling (35%), and dental services (29%) were the supportive services patients most frequently needed. Unmet needs for supportive services were low overall. Significant differences by region in needed and unmet need services were identified.Discussion:The majority of MMP respondents reported standard of care CD4 and viral load monitoring, high treatment use, undetectable HIV viral loads and CD4 counts indicative of good immune function and treatment efficacy. Information from MMP can be used by planning councils, policymakers, and HIV care providers to improve access to care and prevention. Identifying regional differences can facilitate sharing of best practices among health jurisdictions.

Parametric and permutation testing for multivariate monotonic alternatives

We are firstly interested in testing the homogeneity of k mean vectors against two-sided restricted alternatives separately in multivariate normal distributions. This problem is a multivariate extension of Bartholomew (in Biometrica 46:328---335, 1959b) and an extension of Sasabuchi et al. (in Biometrica 70:465---472, 1983) and Kulatunga and Sasabuchi (in Mem. Fac. Sci., Kyushu Univ. Ser. A: Mathematica 38:151---161, 1984) to two-sided ordered hypotheses. We examine the problem of testing under two separate cases. One case is that covariance matrices are known, the other one is that covariance matrices are unknown but common. For the general case that covariance matrices are known the test statistic is obtained using the likelihood ratio method. When the known covariance matrices are common and diagonal, the null distribution of test statistic is derived and its critical values are computed at different significance levels. A Monte Carlo study is also presented to estimate the power of the test. A test statistic is proposed for the case when the common covariance matrices are unknown. Since it is difficult to compute the exact p-value for this problem of testing with the classical method when the covariance matrices are completely unknown, we first present a reformulation of the test statistic based on the orthogonal projections on the closed convex cones and then determine the upper bounds for its p-values. Also we provide a general nonparametric solution based on the permutation approach and nonparametric combination of dependent tests.

Bupropion versus methylphenidate in the treatment of children with attention‐deficit/hyperactivity disorder: randomized double‐blind study

To compare the safety and efficacy of bupropion with methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). In a 6-week randomized double-blind study, 44 patients with a DSM-IV-TR diagnosis of ADHD were randomly assigned to receive bupropion 100-150 mg/day (100 mg/day for <30 kg and 150 mg/day for >30 kg) or methylphenidate 20-30 mg/day. Symptoms were assessed using Teacher and Parent Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) at baseline and weeks 3 and 6. Forty patients had at least one post-baseline measurement, and 38 patients completed the trial. No significant difference was found between the two groups on the Parent and Teacher ADHD-RS-IV scores ([F(1, 38) = 0.266, p = 0.609] and [F(1, 38) = 0.001, p = 0.972], respectively). By week 6, 18 patients (90%) in each group achieved response on the Parent scale (Fisher's exact test p-value = 1.0). With the Teacher ADHD-RS-IV used, eight (40%) patients in the bupropion group and 12 (60%) patients in the methylphenidate group achieved response by week 6 (χ(2) (1) = 1.600, p = 0.206). Headache was observed more frequently in the methylphenidate group. Frequency of other side effects was not significantly different between the two groups. Bupropion has a comparable safety and efficacy profile with methylphenidate in children and adolescents with ADHD.

CAFFEINE AS TREATMENT FOR BRONCHIOLITIS‐RELATED APNOEA

20 August 2011 Dear Editor, The incidence of apnoea in infants with bronchiolitis who are referred to hospitals is 10–25%; affected patients are generally less than 2 months old and a history of prematurity is a significant risk factor.1 Bronchiolitis-related apnoeas generally resolve within 48 h, but recurrent attacks are associated with a higher risk of intubation. Caffeine has been shown in premature infants to reduce the number of apnoeic attacks as well as the need for mechanical ventilation. In those young infants with bronchiolitis-related apnoea, a single loading dose of caffeine, with its long half-life, would thus seem like a reasonable idea, and its use has been reported anecdotally.2,3 As not all the intensivists at our institution are convinced as to the efficacy of caffeine in reducing the likelihood of ventilation in bronchiolitis-related apnoeas, this provided a fortuitous dichotomy of patients separated into those who got caffeine and those that did not. We therefore reviewed retrospectively all patients admitted to our hospital with bronchiolitis-related apnoeas from 1 September 2005 until 31 March 2009 to determine if the use of caffeine did or did not reduce the rate of ventilation. Patients admitted directly to the paediatric intensive care unit (PICU) from outside hospitals were excluded as they were generally already intubated. Of the 25 patients identified, 11 were treated with caffeine and 14 were not. Clinical characteristics of these two groups are shown in Table 1. In those patients who were intubated, recurrent apnoea was one of the main factors. In most UK district general hospitals, non-invasive support with nasal continuous positive airway pressure can be provided, but once intubated, then transfer to a PICU is needed. In an exact binary logistic regression analysis with caffeine as the dependent variable, and chronic lung disease and prematurity as the explanatory variables (LogXact5, Cytel Software Corporation, MA, USA), caffeine had an exact two-sided P-value of 0.0595 for caffeine protecting against the need for mechanical ventilation. Our study was retrospective and had a small sample size, but there was a trend towards benefit from caffeine that almost reached statistical significance despite the small number of infants in the study. We conclude that further investigation is needed of the use caffeine for the treatment of bronchiolitis-related apnoea.

Bladder capacity on preoperative urodynamics may impact outcomes on transobturator male slings

Stress incontinence is frequently seen after prostate surgery. We sought to evaluate preoperative urodynamic (UDS) parameters on functional outcomes after transobturator male sling placement. 49 male patients with stress urinary incontinence (SUI) after radical prostatectomy or transurethral resection of the prostate underwent transobturator sling (TOS) placement from December 2008 through June 2011 (AdVance® and Virtue®). A retrospective review was performed of those patients who underwent preoperative UDS and had a minimum of 6 weeks of follow up. In total 38 patients were identified. There were 28 patients considered a success and 10 patients considered a failure. We then evaluated the preoperative UDS parameters between these two groups to identify potential adverse parameters. Overall success rate was 74% (28/38) with an average follow up of 3 months. Comparing the success and failure groups there was no difference between the pre-operative parameters. On pre-operative UDS, only bladder capacity was found to be significantly lower in those who failed TOS. Univariate comparisons of sling outcomes stratified by bladder capacity tertiles was performed. These values were chosen as they represented the 25th, 50th, and 75th percentiles, respectively. All patients (10/10) with bladder capacities in the top tertile experienced success with the sling, compared to only 62% and 50% of patients in the 50th and 25th tertiles, respectively; these differences were significant (Fisher's exact P-value = 0.044). TOS is an effective therapy for men with SUI. Bladder capacity based on pre-operative UDS may impact the success of the procedure.

Abstract 5064: Cytogenetic and somatic characterization of myeloma tumors from a multi-ethnic cohort

Abstract Previous epidemiological studies have suggested that African Americans (AA) are twice as likely to be diagnosed with and to die from Multiple Myeloma (MM) as compared to European Americans (EA). In recent years, however, mortality rates have become more comparable between these groups. Although socioeconomic factors could play a major role to this potential disparity, biological factors may also be responsible for influencing these differences in either incidence and/or mortality. Here we examined a multi-ethnic cohort of MM tumors to assess potential differences in the frequency of molecular events in tumors derived from either African American (AA) or European American (EA) patients. First, we compared the frequency of 14q32 translocation breakpoints at the IgH locus among a series of data from 115 AA MM patients from three studies and EA MM from the Eastern Cooperative Oncology Group (ECOG). Furthermore, we analyzed matching genome-wide copy number and transcriptional data among 47 AA MM tumors and 196 EA MM tumors to determine differences in the frequency of molecular events in tumors from these populations. Univariate analyses were conducted using the Fisher's Exact Test and p-values were calculated to measure statistical significance. We observed statistically significant differences in the frequency of IgH translocations and somatic copy number alterations. Although we did not detect differences for specific translocation subtypes, we saw a statistically significant difference in the overall frequency of IgH translocations between the two groups, which occurred more frequently in EA patients (p = 0.032). When assessing genomic copy number events previously shown to be associated with poor outcome in MM, chromosome 13 monosomy was more frequent in hyperdiploid MM from AA patients and significant after correcting for multiple testing using the Bonferoni correction method (p = 0.001). Moreover, when using the Benjamini-Hochberg multiple testing correction method, chromosome 13 monosomy remained significantly different among hyperdiploid AA patients (p = 0.0121). Chromosome 1q amplification was also significant among hyperdiploid tumors from EA patients when using this correction method (p = 0.036). No differences in the frequency of hyperdiploid status or gene expression-based subtypes were detected when comparing tumors from AA and EA patients. Our study represents the first comprehensive assessment of the frequency and distribution of molecular alterations in MM tumors from both AA and EA patients and could help shed light on possible biological features associated with population differences in incidence and outcome in MM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5064. doi:1538-7445.AM2012-5064

1830 PROPENSITY SCORE ANALYSIS OF COMPARATIVE EFFECTIVENESS: PERCUTANEOUS NEPHROLITHOTOMY VERSUS STAGED URETEROSCOPY FOR KIDNEY STONES BETWEEN 2 AND 4 CENTIMETERS

You have accessJournal of UrologyStone Disease: New Technology/SWL, Ureteroscopic or Percutaneous Stone Removal III1 Apr 20121830 PROPENSITY SCORE ANALYSIS OF COMPARATIVE EFFECTIVENESS: PERCUTANEOUS NEPHROLITHOTOMY VERSUS STAGED URETEROSCOPY FOR KIDNEY STONES BETWEEN 2 AND 4 CENTIMETERS Emily Scott, Dan Winger, Samih Al-Hayek, Joel Bigley, Khaled Shahrour, Stephen Jackman, and Timothy Averch Emily ScottEmily Scott Pittsburgh, PA More articles by this author , Dan WingerDan Winger Pittsburgh, PA More articles by this author , Samih Al-HayekSamih Al-Hayek Pittsburgh, PA More articles by this author , Joel BigleyJoel Bigley Pittsburgh, PA More articles by this author , Khaled ShahrourKhaled Shahrour Pittsburgh, PA More articles by this author , Stephen JackmanStephen Jackman Pittsburgh, PA More articles by this author , and Timothy AverchTimothy Averch Pittsburgh, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1918AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Historically, the standard for the treatment of large stone burdens is percutaneous nephrolithotomy (PCNL). However, staged ureteroscopy (SURS) is being used more frequently to treat these stones. This study evaluates the comparative effectiveness of these procedures in treating stones between 2 and 4 centimeters in diameter using propensity score analysis. METHODS With IRB approval, all PCNL patients' charts from 2000 to 2010 with stones between 2 and 4 centimeters were reviewed. Patients with staghorn stones were also excluded, as their probability of receiving a PCNL procedure was much greater than an SURS procedure. SURS patients that met the same criteria were selected for between 2005 and 2010. A comparison of the two procedures was performed analyzing complications, hospital length of stay (HLOS), patients requiring a second look, and overall stone free success rate. Propensity score analysis accounted for nonrandom assignment of the two procedures. The propensity scores took into account a variety of risk factors not balanced in the original dataset (I.e. BMI, diabetes, coagulopathy, various stone characteristics, etc.). Propensity scores were used to either construct matched data sets for paired comparisons or to adjust traditional unmatched regression methods. RESULTS 158 PCNL patients and 41 SURS patients with valid data were used, and propensity score analysis with caliper matching was generated into a matched data set of 29 patients in each group. Based on this matched data set, there was no difference in the complication rate of the two procedures (PCNL 6.90%, SURS 3.45%, exact p-value = 1.00). Also, there was no difference in the success of the two procedures (stone free overall, PCNL 89.7%, SURS 86.2%, exact p-value = 1.00). There was a difference, however, in HLOS (PNCL 2.31, SURS 0.03, p-value < 0.001) and in rate of second look (PCNL 37.9%, SURS 89.7%, p-value < 0.001). Other methods of statistical analysis included traditional regression methods adjusting for propensity scores, which used the entire unmatched dataset, and produced the same above conclusions as the matched analysis. CONCLUSIONS The use of propensity score analysis showed no significant difference between PCNL and SURS in complication and stone free rates for stones of this size. PCNL resulted in a longer HLOS, and SURS had a higher rate of second look. The data suggests that SURS should be considered as an alternative treatment in appropriate patients with this magnitude of stone burden. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e740 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Emily Scott Pittsburgh, PA More articles by this author Dan Winger Pittsburgh, PA More articles by this author Samih Al-Hayek Pittsburgh, PA More articles by this author Joel Bigley Pittsburgh, PA More articles by this author Khaled Shahrour Pittsburgh, PA More articles by this author Stephen Jackman Pittsburgh, PA More articles by this author Timothy Averch Pittsburgh, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Rapid and Robust Resampling-Based Multiple-Testing Correction with Application in a Genome-Wide Expression Quantitative Trait Loci Study

Genome-wide expression quantitative trait loci (eQTL) studies have emerged as a powerful tool to understand the genetic basis of gene expression and complex traits. In a typical eQTL study, the huge number of genetic markers and expression traits and their complicated correlations present a challenging multiple-testing correction problem. The resampling-based test using permutation or bootstrap procedures is a standard approach to address the multiple-testing problem in eQTL studies. A brute force application of the resampling-based test to large-scale eQTL data sets is often computationally infeasible. Several computationally efficient methods have been proposed to calculate approximate resampling-based P-values. However, these methods rely on certain assumptions about the correlation structure of the genetic markers, which may not be valid for certain studies. We propose a novel algorithm, rapid and exact multiple testing correction by resampling (REM), to address this challenge. REM calculates the exact resampling-based P-values in a computationally efficient manner. The computational advantage of REM lies in its strategy of pruning the search space by skipping genetic markers whose upper bounds on test statistics are small. REM does not rely on any assumption about the correlation structure of the genetic markers. It can be applied to a variety of resampling-based multiple-testing correction methods including permutation and bootstrap methods. We evaluate REM on three eQTL data sets (yeast, inbred mouse, and human rare variants) and show that it achieves accurate resampling-based P-value estimation with much less computational cost than existing methods. The software is available at http://csbio.unc.edu/eQTL.

Dynamic Markov Bases

This article presents a computational approach for generating Markov bases for multiway contingency tables whose cell counts might be constrained by fixed marginals and by lower and upper bounds. Our framework includes tables with structural zeros as a particular case. Instead of computing the entire Markov bases in an initial step, our framework finds sets of local moves that connect each table in the reference set with a set of neighbor tables. We construct a Markov chain on the reference set of tables that requires only a set of local moves at each iteration. The union of these sets of local moves forms a dynamic Markov basis. We illustrate the practicality of our algorithms in the estimation of exact p-values for a three-way table with structural zeros and a sparse eight-way table. This article has online supplementary materials.

CodingMotif: exact determination of overrepresented nucleotide motifs in coding sequences

BackgroundIt has been increasingly appreciated that coding sequences harbor regulatory sequence motifs in addition to encoding for protein. These sequence motifs are expected to be overrepresented in nucleotide sequences bound by a common protein or small RNA. However, detecting overrepresented motifs has been difficult because of interference by constraints at the protein level. Sampling-based approaches to solve this problem based on codon-shuffling have been limited to exploring only an infinitesimal fraction of the sequence space and by their use of parametric approximations.ResultsWe present a novel O(N(log N)2)-time algorithm, CodingMotif, to identify nucleotide-level motifs of unusual copy number in protein-coding regions. Using a new dynamic programming algorithm we are able to exhaustively calculate the distribution of the number of occurrences of a motif over all possible coding sequences that encode the same amino acid sequence, given a background model for codon usage and dinucleotide biases. Our method takes advantage of the sparseness of loci where a given motif can occur, greatly speeding up the required convolution calculations. Knowledge of the distribution allows one to assess the exact non-parametric p-value of whether a given motif is over- or under- represented. We demonstrate that our method identifies known functional motifs more accurately than sampling and parametric-based approaches in a variety of coding datasets of various size, including ChIP-seq data for the transcription factors NRSF and GABP.ConclusionsCodingMotif provides a theoretically and empirically-demonstrated advance for the detection of motifs overrepresented in coding sequences. We expect CodingMotif to be useful for identifying motifs in functional genomic datasets such as DNA-protein binding, RNA-protein binding, or microRNA-RNA binding within coding regions. A software implementation is available at http://bioinformatics.bc.edu/chuanglab/codingmotif.tar

An effective statistical evaluation of ChIPseq dataset similarity

ChIPseq is rapidly becoming a common technique for investigating protein-DNA interactions. However, results from individual experiments provide a limited understanding of chromatin structure, as various chromatin factors cooperate in complex ways to orchestrate transcription. In order to quantify chromtain interactions, it is thus necessary to devise a robust similarity metric applicable to ChIPseq data. Unfortunately, moving past simple overlap calculations to give statistically rigorous comparisons of ChIPseq datasets often involves arbitrary choices of distance metrics, with significance being estimated by computationally intensive permutation tests whose statistical power may be sensitive to non-biological experimental and post-processing variation. We show that it is in fact possible to compare ChIPseq datasets through the efficient computation of exact P-values for proximity. Our method is insensitive to non-biological variation in datasets such as peak width, and can rigorously model peak location biases by evaluating similarity conditioned on a restricted set of genomic regions (such as mappable genome or promoter regions). Applying our method to the well-studied dataset of Chen et al. (2008), we elucidate novel interactions which conform well with our biological understanding. By comparing ChIPseq data in an asymmetric way, we are able to observe clear interaction differences between cofactors such as p300 and factors that bind DNA directly. Source code is available for download at http://sonorus.princeton.edu/IntervalStats/IntervalStats.tar.gz. Supplementary data are available at Bioinformatics online.

Methods for Determining the Statistical Significance of Enrichment or Depletion of Gene Ontology Classifications under Weighted Membership

High-throughput molecular biology studies, such as microarray assays of gene expression, two-hybrid experiments for detecting protein interactions, or ChIP-Seq experiments for transcription factor binding, often result in an “interesting” set of genes – say, genes that are co-expressed or bound by the same factor. One way of understanding the biological meaning of such a set is to consider what processes or functions, as defined in an ontology, are over-represented (enriched) or under-represented (depleted) among genes in the set. Usually, the significance of enrichment or depletion scores is based on simple statistical models and on the membership of genes in different classifications. We consider the more general problem of computing p-values for arbitrary integer additive statistics, or weighted membership functions. Such membership functions can be used to represent, for example, prior knowledge on the role of certain genes or classifications, differential importance of different classifications or genes to the experimenter, hierarchical relationships between classifications, or different degrees of interestingness or evidence for specific genes. We describe a generic dynamic programming algorithm that can compute exact p-values for arbitrary integer additive statistics. We also describe several optimizations for important special cases, which can provide orders-of-magnitude speed up in the computations. We apply our methods to datasets describing oxidative phosphorylation and parturition and compare p-values based on computations of several different statistics for measuring enrichment. We find major differences between p-values resulting from these statistics, and that some statistics recover “gold standard” annotations of the data better than others. Our work establishes a theoretical and algorithmic basis for far richer notions of enrichment or depletion of gene sets with respect to gene ontologies than has previously been available.

Ex vivocomparison of Galileos cone beam CT and intraoral radiographs in detecting occlusal caries

The aim of this study was to compare the accuracy of cone beam CT (CBCT) with intraoral radiographs for detection of occlusal caries. A set of 60 extracted teeth were imaged using a Sirona Galileos CBCT system (Sirona Dental Systems, Bensheim, Germany) and an intraoral Planmeca® system (Planmeca OY, Helsinki, Finland). Six observers looked at both modalities and used a five-point confidence scale to evaluate presence or absence of occlusal caries. Histology was used as the gold standard. Receiver operating characteristic analysis and weighted kappa statistics were used for statistical analysis. Differences in the area under the curve (AUC) values between observers and modalities were analysed using analysis of variance (ANOVA). Differences in sensitivity and specificity were analysed using the Wilcoxon test. Interobserver and intraobserver reliability was assessed by weighted kappa scores. The mean value and standard deviation of AUC was 0.719 ± 0.038 for CBCT and 0.649 ± 0.062 for the intraoral radiographs. The ANOVA results demonstrated that there was no significant difference between the modalities and the observers. The interobserver kappa for pairs of observers ranged from fair to substantial for bitewings (0.244-0.543) and CBCT (0.152-0.401). Four out of six observers reported higher sensitivity but lower specificity with CBCT. The Wilcoxon exact p-value showed no difference in sensitivity (0.175) or specificity (0.573) between the two modalities. Based on the results we conclude that the Sirona CBCT unit cannot be used for the sole purpose of looking at occlusal caries.