Exact P-value Research Articles

Confidence intervals based on some weighting functions for the difference of two binomial proportions

In this paper, we propose two new methods for computing confidence intervals for the difference of two independent binomial proportions in small sample cases. Several test-based exact confidence intervals have been developed to guarantee the nominal coverage probability in small sample cases. However, these methods are sometimes unnecessarily too conservative because they use the exact p-value for constructing confidence intervals by maximizing the tail probability to account for the worst configuration. In order to reduce conservatism, our new methods adopt the p-value weighted by two types of functions instead of the maximum p-value. Our proposed methods can be regarded as quasi-exact methods. The performance evaluation results showed that our methods are much less conservative than the exact method. Compared with other existing quasi-exact methods, generally, our methods possess coverage probabilities closer to the nominal confidence level and shorter expected confidence widths. In particular, the beta weighing method provides the most reasonable balance between accurate coverage probability and short interval width in small sample cases.

A123: HLA Associations in a Matched Cohort of Juvenile Idiopathic Arthritis Children With and Without Uveitis

Background/Purpose:Studies have shown that HLA‐DRB1*8, 11 and 13 are strong risk alleles for various juvenile idiopathic arthritis (JIA) subtypes. There are few studies investigating the role of HLADRB1 alleles in children with uveitis. Our objective is to determine the association of these alleles with uveitis in a matched cohort of children with JIA and JIAassociated uveitis (JIA‐U). We will also explore associations with uveitis complications and the need for antitumor necrosis factor (TNF) agents.Methods:We matched children with JIA and JIA‐U on race, ethnicity, sex, age at arthritis diagnosis, and JIA subtype. We included Non‐Hispanic White (NHW) controls. We performed high‐resolution HLADRB1 genotyping. Odds ratios and 95% confidence intervals are presented. In some instances, exact confidence intervals and p‐value are provided due to small sample sizes.Results:There were 373 controls, 43 children with JIA‐U and 48 with JIA of whom 37 were matched. Each matched group had 29 (78.4%) females and 28 children with oligoarticular (6 extended, 22 persistent) and 9 polyarticular rheumatoid factor (RF) negative JIA.In our matched analysis comparing children with JIA‐U and JIA, there was a difference in the frequency of carriage of DRB1*11 (35.1% vs. 18.9%) and both DRB1*11 and DRB1*13 alleles (16.2% vs. 2.7%) which approached significance, reflecting our modest sample size (OR 2.32, p = 0.116 and OR 6.97, p = 0.107, respectively).In comparison with controls, children with JIA and JIA‐U had increased odds of having DRB1*8 (OR 5.54, p < 0.001 and OR 9.00, p < 0.001, respectively) and DRB1*13 (OR 2.38, p = 0.005 and OR 2.40, p = 0.007). Additionally, compared to controls, children with JIA and JIA‐U had greater odds of having at least one of the following: DRB1*8, 11 or 13 (OR 4.27, p < 0.001 and OR 5.37, p < 0.001) and DRB1*11 or 13 (OR 2.30, p = 0.006 and OR 2.29, p = 0.010). Only children with JIA‐U had increased odds of having DRB1*11 (OR = 2.22, p = 0.024), and carriage of both DRB1*11 and 13 (OR 9.92, p < 0.001).No increase in allele frequency was noted with regards to ocular complications or the use of anti‐TNF agents in children with JIA‐U. Comparison of HLA‐DRB1 in children with JIA and JIA‐U HLA Configuration % OR p value Matched JIA (N = 37) vs JIA‐U (N = 37) JIA (N = 48) vs controls JIA‐U (N = 43) vs controls DRB1*8 21.6% vs. 27.0% 22.9% vs. 5.1% 32.6% vs. 5.1% OR 1.34 OR 5.54 OR 9.00 P=NS P<0.001 P <0.001 DRB1*11 18.9% vs. 35.1% 18.9% vs. 16.4% 30.2% vs. 16.4% OR 2.32 OR 1.18 OR 2.22 P=0.116 P=NS P=0.024 DRB1*13 54.1% vs. 54.1% 41.7% vs. 23.1% 41.9% vs. 23.1% OR 1.000 OR 2.38 OR 2.40 P=NS P=0.005 P=0.007 DRB1*8, 11 or 13 78.4% vs. 81.1% 75.0% vs. 41.3% 79.1% vs. 41.3% OR 1.18 OR 4.27 OR 5.37 P=NS P <0.001 P <0.001 DRB1*11 or 13 64.9% vs. 62.2% 58.3% vs. 37.8% 58.1% vs. 37.8% OR 1.12 OR 2.30 OR 2.29 P=NS P=0.006 P=0.010 DRB1*11/8 2.7% vs. 5.4% 4.2% vs. 1.1% 4.7% vs. 1.1% OR 2.06 OR 3.95 OR 4.50 P=NS P=NS P=NS DRB1*11/13 2.7% vs. 16.2% 2.1% vs. 1.6% 14.0% vs. 1.6% OR 6.97 OR 1.30 OR 9.92 P=0.107 P=NS p<0.001 DRB1*13/8 2.7% vs. 5.4% 2.1% vs. 0.5% 7.0% vs. 0.5% OR 2.06 OR 3.95 OR 13.91 P=NS P=NS P=0.009 NS = not significantConclusion:This is the first matched analysis of children with JIA and JIA‐U. Carriage of both DRB1*11 and 13 appear to increase the risk for developing uveitis. Further studies should be conducted in a larger matched cohort of children with JIA, and the role of HLA in the risk for ocular complications and severe disease should be considered.

Association of HLA-DPB1 with Scleroderma and Its Clinical Features in Chinese Population

Human leukocyte antigen DPB1 was reported to contain singly nucleotide polymorphisms conferring the strongest susceptibility to systemic sclerosis in Korean population. However, associations of specific DPB1 alleles with SSc vary in different ethnic populations. The aim of this study was to profile DPB1 alleles in Chinese population and to identify specific DPB1 alleles in association with SSc and clinical and serological features of SSc in Han Chinese. A cohort containing 338 patients with SSc and 480 gender-matched and unrelated controls were examined in the study. The HLA-DPB1 genotyping was performed with sequence-based typing method. Exact p-values were obtained (Fisher's test) from 2×2 tables of allele counts or allele carriers and disease status. Thirty eight DPB1 alleles were found in the cohort. DPB1*05:01 was the most common allele in this cohort. DPB1*03:01 and *13:01 were significantly increased in SSc. DPB1*13:01 association had already been described in other ethnic populations, whereas DPB1*03:01 was specific to Han Chinese patients with SSc. In addition, comparisons between SSc subsets indicated that patients carrying DPB1*03:01 were more likely to develop pulmonary fibrosis, DPB1*04 carriers were increased in SSc patients with anti-centromere autoantibodies and in contrast, SSc patients with homozygous DPB1*05:01 showed an opposite association with marginal significance.

P-values for the Discrete Scan Statistic through Slack Variables

The discrete scan statistic is used in many areas of applied probability and statistics to study local clumping of patterns. Testing based on the statistic requires tail probabilities. Whereas the distribution has been studied extensively, most of the results are approximations, due to the difficulties associated with the computation. Results for exact p-values for the statistic have been given for a binary sequence that is independent or first-order Markovian. We give an algorithm to obtain probabilities for the statistic over multi-state trials that are Markovian of a general order of dependence, and explore the algorithm's usefulness.

Transcriptome-Wide Analysis of UTRs in Non-Small Cell Lung Cancer Reveals Cancer-Related Genes with SNV-Induced Changes on RNA Secondary Structure and miRNA Target Sites

Traditional mutation assessment methods generally focus on predicting disruptive changes in protein-coding regions rather than non-coding regulatory regions like untranslated regions (UTRs) of mRNAs. The UTRs, however, are known to have many sequence and structural motifs that can regulate translational and transcriptional efficiency and stability of mRNAs through interaction with RNA-binding proteins and other non-coding RNAs like microRNAs (miRNAs). In a recent study, transcriptomes of tumor cells harboring mutant and wild-type KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) genes in patients with non-small cell lung cancer (NSCLC) have been sequenced to identify single nucleotide variations (SNVs). About 40% of the total SNVs (73,717) identified were mapped to UTRs, but omitted in the previous analysis. To meet this obvious demand for analysis of the UTRs, we designed a comprehensive pipeline to predict the effect of SNVs on two major regulatory elements, secondary structure and miRNA target sites. Out of 29,290 SNVs in 6462 genes, we predict 472 SNVs (in 408 genes) affecting local RNA secondary structure, 490 SNVs (in 447 genes) affecting miRNA target sites and 48 that do both. Together these disruptive SNVs were present in 803 different genes, out of which 188 (23.4%) were previously known to be cancer-associated. Notably, this ratio is significantly higher (one-sided Fisher's exact test p-value = 0.032) than the ratio (20.8%) of known cancer-associated genes (n = 1347) in our initial data set (n = 6462). Network analysis shows that the genes harboring disruptive SNVs were involved in molecular mechanisms of cancer, and the signaling pathways of LPS-stimulated MAPK, IL-6, iNOS, EIF2 and mTOR. In conclusion, we have found hundreds of SNVs which are highly disruptive with respect to changes in the secondary structure and miRNA target sites within UTRs. These changes hold the potential to alter the expression of known cancer genes or genes linked to cancer-associated pathways.

A fast algorithm for determining bounds and accurate approximate p -values of the rank product statistic for replicate experiments

The rank product method is a powerful statistical technique for identifying differentially expressed molecules in replicated experiments. A critical issue in molecule selection is accurate calculation of the p-value of the rank product statistic to adequately address multiple testing. Both exact calculation and permutation and gamma approximations have been proposed to determine molecule-level significance. These current approaches have serious drawbacks as they are either computationally burdensome or provide inaccurate estimates in the tail of the p-value distribution. We derive strict lower and upper bounds to the exact p-value along with an accurate approximation that can be used to assess the significance of the rank product statistic in a computationally fast manner. The bounds and the proposed approximation are shown to provide far better accuracy over existing approximate methods in determining tail probabilities, with the slightly conservative upper bound protecting against false positives. We illustrate the proposed method in the context of a recently published analysis on transcriptomic profiling performed in blood. We provide a method to determine upper bounds and accurate approximate p-values of the rank product statistic. The proposed algorithm provides an order of magnitude increase in throughput as compared with current approaches and offers the opportunity to explore new application domains with even larger multiple testing issue. The R code is published in one of the Additional files and is available at http://www.ru.nl/publish/pages/726696/rankprodbounds.zip .

Suffer the Little Children: A Painful Truth

Applied Kinesiology (AK) is a diagnostic technique widely used within the Integrative Medical community. In essence, it posits that a question can be mentally held in a person’s mind, sometimes while they are holding a substance like a vitamin, or a food sample, and by measuring relative muscular weakness an answer as to whether the substance or the condition represented by the question is good for that person can be obtained. This AK is presumed to have a diagnostic capability. That being presumed, this study asks the following questions: (1) Is there a difference in muscular strength when an individual holds a substance that is inimical to life processes (a poison solution), as compared to a substance that is essential for life (normal saline)? (2) Is this effect a transaction involving input from both the person being measured and the kinesiologist doing the measurement or is it only the person being measured? (3) As an extension of question 2, is the result the same when different kinesiologists take the measurement or when no kinesiologist is involved? (4) Does belief, expectation, gender, or time cognition play a role in determining response?To answer these questions, which would help to define the parameters of the AK process, 51 participants were tested during three trials each, first by one kinesiologist, then by another, and finally, with no kinesiologist present by grip strength indicated using a hand dynamometer. Grip strength being a self-administered AK test of relative muscular strength. For each trial, a pair of randomly numbered sealed vials, each pair in a randomly numbered plastic bag, were used as the objects of the trial. In each bag, one vial contained saline solution while the other was filled with a slightly smaller amount of saline solution to which had been added ionic hydroxylamine hydrochloride (NH3OH)+, producing a toxic solution of 9 mg/ml. Each trial consisted of a separate muscle test for each vial. All present at the trials were blind as to which vial contained the toxin. And all who prepared the vials were blind to the trials. The force used by the kinesiologists in each of their trials was measured via a pressure pad system. The hand dynamometer trials were conducted with no kinesiologist present.Of the 151 sets of trials, the toxic vial was identified correctly in 80 of them (53%), resulting in a one-tailed exact binomial P-value of .258. Results for two of the kinesiologists were almost exactly at chance. For the third kinesiologist, there was a one-tailed exact binomial P-value of .18 (unadjusted for multiple testing). Results for the dynamometer were also almost exactly at chance. Testing whether there was a significant difference in proportions for whom the AK test worked based on belief about whether it would work resulted in non-significant χ2 values of 0.6 (P = .439) for the trials with one kinesiologist and 2.222 (P = .136) for the hand dynamometer trials. The final variable examined was gender. While there was no significant difference in performance for males and females for the trials of the male kinesiologist or the hand dynamometer, the combined data for the two female kinesiologists did reveal a difference. Of the 33 sessions with females, only 15 were successful (45%), while for the 18 sessions with males, 14 were successful (78%), resulting in a χ2 statistic of 4.96, P = .026. However, given all of the χ2 tests performed in this section, the results must be interpreted with caution because of multiple testing. Results indicate belief in whether the AK test will work was not significantly related to whether it actually did work. A χ2 test of the relationship between time perception and correct vial choice showed no significant relationships. The χ2 statistic for the relationship using the hand dynamometer data was 0.927, P = .629.The data in this study, particularly when seen in the larger context of a review of the literature from the AK field itself by Klinkoski and Leboeuf (1990), which considered 50 papers published between 1981 and 1987 by the International College of Applied Kinesiology, and the survey by Hall, Lewith, Brien, and Little (2008), using standard evaluation criteria [quality assessment tool for studies of diagnostic accuracy included in systematic reviews (QUADAS), Standards for Reporting of Diagnostic Studies (STARD), JADAD, and Consolidated Standards of Reporting Trials (CONSORT)], for research methodology, as well as six prior non-clinical studies by Radin (1984), Quintanar and Hill (1988), Braud (1989), Arnett et al. (1999), Ludtke (2001), and Kendler and Keating (2003), all together suggest the following: The research published by the Applied Kinesiology field itself is not to be relied upon, and in the experimental studies that do meet accepted standards of science, Applied Kinesiology has not demonstrated that it is a useful or reliable diagnostic tool upon which health decisions can be based.

A Double-Blind, Randomized Study to Assess the Validity of Applied Kinesiology (AK) as a Diagnostic Tool and as a Nonlocal Proximity Effect

Applied Kinesiology (AK) is a diagnostic technique widely used within the Integrative Medical community. In essence, it posits that a question can be mentally held in a person's mind, sometimes while they are holding a substance like a vitamin, or a food sample, and by measuring relative muscular weakness an answer as to whether the substance or the condition represented by the question is good for that person can be obtained. This AK is presumed to have a diagnostic capability. That being presumed, this study asks the following questions: (1) Is there a difference in muscular strength when an individual holds a substance that is inimical to life processes (a poison solution), as compared to a substance that is essential for life (normal saline)? (2) Is this effect a transaction involving input from both the person being measured and the kinesiologist doing the measurement or is it only the person being measured? (3) As an extension of question 2, is the result the same when different kinesiologists take the measurement or when no kinesiologist is involved? (4) Does belief, expectation, gender, or time cognition play a role in determining response?To answer these questions, which would help to define the parameters of the AK process, 51 participants were tested during three trials each, first by one kinesiologist, then by another, and finally, with no kinesiologist present by grip strength indicated using a hand dynamometer. Grip strength being a self-administered AK test of relative muscular strength. For each trial, a pair of randomly numbered sealed vials, each pair in a randomly numbered plastic bag, were used as the objects of the trial. In each bag, one vial contained saline solution while the other was filled with a slightly smaller amount of saline solution to which had been added ionic hydroxylamine hydrochloride (NH3OH)(+), producing a toxic solution of 9mg/ml. Each trial consisted of a separate muscle test for each vial. All present at the trials were blind as to which vial contained the toxin. And all who prepared the vials were blind to the trials. The force used by the kinesiologists in each of their trials was measured via a pressure pad system. The hand dynamometer trials were conducted with no kinesiologist present.Of the 151 sets of trials, the toxic vial was identified correctly in 80 of them (53%), resulting in a one-tailed exact binomial P-value of .258. Results for two of the kinesiologists were almost exactly at chance. For the third kinesiologist, there was a one-tailed exact binomial P-value of .18 (unadjusted for multiple testing). Results for the dynamometer were also almost exactly at chance. Testing whether there was a significant difference in proportions for whom the AK test worked based on belief about whether it would work resulted in non-significant χ(2) values of 0.6 (P = .439) for the trials with one kinesiologist and 2.222 (P = .136) for the hand dynamometer trials. The final variable examined was gender. While there was no significant difference in performance for males and females for the trials of the male kinesiologist or the hand dynamometer, the combined data for the two female kinesiologists did reveal a difference. Of the 33 sessions with females, only 15 were successful (45%), while for the 18 sessions with males, 14 were successful (78%), resulting in a χ(2) statistic of 4.96, P = .026. However, given all of the χ(2) tests performed in this section, the results must be interpreted with caution because of multiple testing. Results indicate belief in whether the AK test will work was not significantly related to whether it actually did work. A χ(2) test of the relationship between time perception and correct vial choice showed no significant relationships. The χ(2) statistic for the relationship using the hand dynamometer data was 0.927, P = .629.The data in this study, particularly when seen in the larger context of a review of the literature from the AK field itself by Klinkoski and Leboeuf (1990), which considered 50 papers published between 1981 and 1987 by the International College of Applied Kinesiology, and the survey by Hall, Lewith, Brien, and Little (2008), using standard evaluation criteria [quality assessment tool for studies of diagnostic accuracy included in systematic reviews (QUADAS), Standards for Reporting of Diagnostic Studies (STARD), JADAD, and Consolidated Standards of Reporting Trials (CONSORT)], for research methodology, as well as six prior non-clinical studies by Radin (1984), Quintanar and Hill (1988), Braud (1989), Arnett et al. (1999), Ludtke (2001), and Kendler and Keating (2003), all together suggest the following: The research published by the Applied Kinesiology field itself is not to be relied upon, and in the experimental studies that do meet accepted standards of science, Applied Kinesiology has not demonstrated that it is a useful or reliable diagnostic tool upon which health decisions can be based.

Characterizing concentrations of diethylene glycol and suspected metabolites in human serum, urine, and cerebrospinal fluid samples from the Panama DEG mass poisoning

Context. Diethylene glycol (DEG) mass poisoning is a persistent public health problem. Unfortunately, there are no human biological data on DEG and its suspected metabolites in poisoning. If present and associated with poisoning, the evidence for use of traditional therapies such as fomepizole and/or hemodialysis would be much stronger. Objective. To characterize DEG and its metabolites in stored serum, urine, and cerebrospinal fluid (CSF) specimens obtained from human DEG poisoning victims enrolled in a 2006 case-control study. Methods. In the 2006 study, biological samples from persons enrolled in a case-control study (42 cases with new-onset, unexplained AKI and 140 age-, sex-, and admission date-matched controls without AKI) were collected and shipped to the Centers for Disease Control and Prevention (CDC) in Atlanta for various analyses and were then frozen in storage. For this study, when sufficient volume of the original specimen remained, the following analytes were quantitatively measured in serum, urine, and CSF: DEG, 2-hydroxyethoxyacetic acid (HEAA), diglycolic acid, ethylene glycol, glycolic acid, and oxalic acid. Analytes were measured using low resolution GC/MS, descriptive statistics calculated and case results compared with controls when appropriate. Specimens were de-identified so previously collected demographic, exposure, and health data were not available. The Wilcoxon Rank Sum test (with exact p-values) and bivariable exact logistic regression were used in SAS v9.2 for data analysis. Results. The following samples were analyzed: serum, 20 case, and 20 controls; urine, 11 case and 22 controls; and CSF, 11 samples from 10 cases and no controls. Diglycolic acid was detected in all case serum samples (median, 40.7 mcg/mL; range, 22.6–75.2) and no controls, and in all case urine samples (median, 28.7 mcg/mL; range, 14–118.4) and only five (23%) controls (median, < Lower Limit of Quantitation (LLQ); range, < LLQ–43.3 mcg/mL). Significant differences and associations were identified between case status and the following: 1) serum oxalic acid and serum HEAA (both OR = 14.6; 95% C I = 2.8–100.9); 2) serum diglycolic acid and urine diglycolic acid (both OR > 999; exact p < 0.0001); and 3) urinary glycolic acid (OR = 0.057; 95% C I = 0.001–0.55). Two CSF sample results were excluded and two from the same case were averaged, yielding eight samples from eight cases. Diglycolic acid was detected in seven (88%) of case CSF samples (median, 2.03 mcg/mL; range, < LLQ, 7.47). Discussion. Significantly elevated HEAA (serum) and diglycolic acid (serum and urine) concentrations were identified among cases, which is consistent with animal data. Low urinary glycolic acid concentrations in cases may have been due to concurrent AKI. Although serum glycolic concentrations among cases may have initially increased, further metabolism to oxalic acid may have occurred thereby explaining the similar glycolic acid concentrations in cases and controls. The increased serum oxalic acid concentration results in cases versus controls are consistent with this hypothesis. Conclusion. Diglycolic acid is associated with human DEG poisoning and may be a biomarker for poisoning. These findings add to animal data suggesting a possible role for traditional antidotal therapies. The detection of HEAA and diglycolic acid in the CSF of cases suggests a possible association with signs and symptoms of DEG-associated neurotoxicity. Further work characterizing the pathophysiology of DEG-associated neurotoxicity and the role of traditional toxic alcohol therapies such as fomepizole and hemodialysis is needed.

Pressure relieving support surfaces: a randomised evaluation 2 (PRESSURE 2)

Background: Pressure ulcers (PUs) are a burden to patients, carers and health-care providers. Specialist mattresses minimise the intensity and duration of pressure on vulnerable skin sites in at-risk patients. Primary objective: Time to developing a new PU of category ≥ 2 in patients using an alternating pressure mattress (APM) compared with a high-specification foam mattress (HSFM). Design: A multicentre, Phase III, open, prospective, planned as an adaptive double-triangular group sequential, parallel-group, randomised controlled trial with an a priori sample size of 2954 participants. Randomisation used minimisation (incorporating a random element). Setting: The trial was set in 42 secondary and community inpatient facilities in the UK. Participants: Adult inpatients with evidence of acute illness and at a high risk of PU development. Interventions and follow-up: APM or HSFM – the treatment phase lasted a maximum of 60 days; the final 30 days were post-treatment follow-up. Main outcome measures: Time to event. Results: From August 2013 to November 2016, 2029 participants were randomised to receive either APM (n = 1016) or HSFM (n = 1013). Primary end point – 30-day final follow-up: of the 2029 participants in the intention-to-treat population, 160 (7.9%) developed a new PU of category ≥ 2. There was insufficient evidence of a difference between groups for time to new PU of category ≥ 2 [Fine and Gray model HR 0.76, 95% confidence interval (CI) 0.56 to 1.04; exact p-value of 0.0890 and 2% absolute difference]. Treatment phase sensitivity analysis: 132 (6.5%) participants developed a new PU of category ≥ 2 between randomisation and end of treatment phase. There was a statistically significant difference in the treatment phase time-to-event sensitivity analysis (Fine and Gray model HR 0.66, 95% CI 0.46 to 0.93; p = 0.0176 and 2.6% absolute difference). Secondary end points – 30-day final follow-up: new PUs of category ≥ 1 developed in 350 (17.2%) participants, with no evidence of a difference between mattress groups in time to PU development, (Fine and Gray model HR 0.83, 95% CI 0.67 to 1.02; p-value = 0.0733 and absolute difference 3.1%). New PUs of category ≥ 3 developed in 32 (1.6%) participants with insufficient evidence of a difference between mattress groups in time to PU development (Fine and Gray model HR 0.81, 95% CI 0.40 to 1.62; p = 0.5530 and absolute difference 0.4%). Of the 145 pre-existing PUs of category 2, 89 (61.4%) healed – there was insufficient evidence of a difference in time to healing (Fine and Gray model HR 1.12, 95% CI 0.74 to 1.68; p = 0.6122 and absolute difference 2.9%). Health economics – the within-trial and long-term analysis showed APM to be cost-effective compared with HSFM; however, the difference in costs models are small and the quality-adjusted life-year gains are very small. There were no safety concerns. Blinded photography substudy – the reliability of central blinded review compared with clinical assessment for PUs of category ≥ 2 was ‘very good’ (kappa statistic 0.82, prevalence- and bias-adjusted kappa 0.82). Quality-of-life substudy – the Pressure Ulcer Quality of Life – Prevention (PU-QoL-P) instrument meets the established criteria for reliability, construct validity and responsiveness. Limitations: A lower than anticipated event rate. Conclusions: In acutely ill inpatients who are bedfast/chairfast and/or have a category 1 PU and/or localised skin pain, APMs confer a small treatment phase benefit that is diminished over time. Overall, the APM patient compliance, very low PU incidence rate observed and small differences between mattresses indicate the need for improved indicators for targeting of APMs and individualised decision-making. Decisions should take into account skin status, patient preferences (movement ability and rehabilitation needs) and the presence of factors that may be potentially modifiable through APM allocation, including being completely immobile, having nutritional deficits, lacking capacity and/or having altered skin/category 1 PU. Future work: Explore the relationship between mental capacity, levels of independent movement, repositioning and PU development. Explore ‘what works for whom and in what circumstances’. Trial registration: Current Controlled Trials ISRCTN01151335. Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 52. See the NIHR Journals Library website for further project information.

Large deviation properties for patterns

Deciding whether a given pattern is over- or under-represented according to a given background model is a key question in computational biology. Such a decision is usually made by computing some p-values reflecting the “exceptionality” of a pattern in a given sequence or set of sequences. In the simplest cases (short and simple patterns, simple background model, small number of sequences), an exact p-value can be computed with a tractable complexity. The realistic cases are in general too complicated to get such an exact p-value. Approximations are thus proposed (Gaussian, Poisson, Large deviation approximations). These approximations are applicable under some conditions: Gaussian approximations are valid in the central domain while Poisson and Large deviation approximations are valid for rare events. In the present paper, we prove a large deviation approximation to the double strands counting problem that refers to a counting of a given pattern in a set of sequences that arise from both strands of the genome. In that case, dependencies between a sequence and its reverse complement cannot be neglected. They are captured here for a Bernoulli model from general combinatorial properties of the pattern. A large deviation result is also provided for a set of small sequences.

Discussion: An estimate of the science-wise false discovery rate and application to the top medical literature

It is a pleasure to have the opportunity to comment on this contribution by Jager and Leek (2013), perhaps the first broad-based empirical attempt to examine the now 8-year-old claim that most conclusions in the medical literature are false (Ioannidis, 2005). The latter paper has had considerable traction, reportedly being the most downloaded article in the history of PLoS Medicine. Its potential positive impact was more wariness about blithely accepting the results of published studies, better understanding of the factors that lead to misleading research, and more awareness of the domain of meta-research. The potential negative impact of the claim was an unwarranted degree of skepticism, hopefully not cynicism, about truth claims in medical science. So, exploring that hypothesis further using empirical data was much needed. But before commenting on Jager and Leek’s contribution, it is useful to understand the assumptions and methodology that supported the original claim, outlined in detail in 2007 (Goodman and Greenland, 2007). Ioannidis’s argument was based on simple Bayesian mathematics, the same kind used in diagnostic studies. However, two elements were incorporated that had the mathematical effect of nullifying research evidence. First, the information from an experiment used in his model was simply P <0.05, not the exact P-value. Thus, an epidemiologic study generating a main finding with a P <0.0001 was treated in that model identically to one with P =0.04. Quantitatively, for a study with 80% power, this reduced the maximum Bayes factor—the degree to which an experiment raises the prior odds of the alternative hypothesis— from infinity to 16.

Improving the reporting of P‐values generated by randomization methods

Summary We increasingly calculate P‐values using randomization approaches. Often, it is not possible to consider full evaluation of all possible samples (e.g. permutations or bootstraps) in order to get an exact P‐value, so an approximate P‐value is calculated across a random sample of these possible samples. We provide methods that allow the uncertainty introduced by this approximation to be compactly and clearly presented. If the recommendations proposed here are adopted, then reviewers and readers of the increasing number of publications using these approaches will be better informed.

범주형 자료에서 순서화된 대립가설 검정을 위한 정확검정의 개발

범주형 자료에서 순서화된 대립가설을 검정하는 경우는 의학 사회학 경영학 등 다양한 응용분야에서 발생한다. 이러한 검정 방법은 대부분 대표본이론에 근거하여 개발되었다. 하지만 표본크기가 작거나 표본크기가 매우 불균등한 경우 대표본이론에 근거한 검정방법의 제 1종 오류 확률은 목표로 하는 5%와 멀어지는 경우가 많이 발생한다. 본 논문에서는 범주형 자료에서 순서화된 대립가설을 검정하는 경우 표본크기가 작거나 표본크기가 매우 불균등한 경우에 사용될 수 있는 정확검정방법을 소개하고 이에 대한 검정력 및 정확 p-value를 제시할 것이다. Testing of order-restricted alternative hypothesis in <TEX>$2{\times}k$</TEX> contingency tables can be applied to various fields of medicine, sociology, and business administration. Most testing methods have been developed based on a large sample theory. In the case of a small sample size or unbalanced sample size, the Type I error rate of the testing method (based on a large sample theory) is very different from the target point of 5%. In this paper, the exact testing method is introduced in regards to the testing of an order-restricted alternative hypothesis in categorical data (particularly if a small sample size or extreme unbalanced data). Power and exact p-value are calculated, respectively.

Statistical power, effect size and animal welfare: recommendations for good practice

AbstractDespite the particular relevance of statistical power to animal welfare studies, we noticed an apparent lack of sufficient information reported in papers published inAnimal Welfareto facilitatepost hoccalculation of statistical power for use in meta-analyses. We therefore conducted a survey of all papers published inAnimal Welfarein 2009 to assess compliance with relevant instructions to authors, the level of statistical detail reported and the interpretation of results regarded as statistically non-significant. In general, we found good levels of compliance with the instructions to authors except in relation to the level of detail reported for the results of each test. Although not requested in the instructions to authors, exactP-values were reported in just over half of the tests but effect size was not explicitly reported for any test, there was no reporting ofa prioristatistical analyses to determine sample size and there was no formal assessment of non-significant results in relation to type II errors. As a first stage to addressing this we recommend more reporting ofa prioripower analyses, more comprehensive reporting of the results of statistical analysis and the explicit consideration of possible statistical power issues when interpretingP-values. We also advocate the calculation of effect sizes and their confidence intervals and a greater emphasis on the interpretation of the biological significance of results rather than just their statistical significance. This will enhance the efforts that are currently being made to comply with the 3Rs, particularly the principle of reduction.

Association of HLA-DQB1*0501 with Scleroderma and its Clinical Features in Chinese Population

Specific human leukocyte antigen (HLA) DQB1 alleles confer strong susceptibility to systemic sclerosis (SSc). However, the frequencies of specific DQB1 alleles and their associations with SSc vary according to ethnicity and clinical features of SSc. The aim of this study was to profile DQB1 alleles in a Chinese population and to identify specific DQB1 alleles in association with SSc of Han Chinese. A cohort containing 213 patients with SSc and 239 gender-matched and unrelated controls was examined in the study. The HLA-DQB1 genotyping was performed with sequence-based typing (SBT) method. Exact p-values were obtained (Fisher's test) from 2x2 tables of allele counts or allele carriers and disease status. Seventeen DQB1 alleles were found in the cohort. DQB1*03:03 was the most common allele in this cohort. DQB1*05:01 was significantly increased in SSc, and was strongly associated with anti-centromere autoantibodies (ACA). Compared with SSc in other ethnic populations, SSc patients of Han Chinese are distinct in association with DQB1*06:11, common in association with DQB1*05:01, but lack association with DQB1*03:01. In addition, DQB1*06:01 appeared more common in ATA-positive Chinese SSc, and marginally associated with pulmonary fibrosis, and an increased frequency of DQB1*03:03 was observed in anti-U1RNP-positive Chinese SSc patients.

O-028 Outcomes in Patients with Acute Ischaemic Stroke from Proximal Intracranial Vessel Occlusion and NIHSS Score Below 8

Background and PurposeAcute ischaemic stroke due to proximal intracranial vessel occlusion is associated with poor prognosis and neurologic outcomes. Outcomes specifically in patients with stroke due to these occlusions and...

P3.430* Doxycycline prophylaxis for syphilis in a persistently high risk HIV infected population

BackgroundSyphilis infections increase spread of HIV. This pilot study investigated the feasibility of conducting a large, randomised trial to determine whether prophylactic doxycycline can reduce incident syphilis among HIV+ men...

Upper Bound for p-Value of the Test of Multivariate Normal Ordered Mean Vectors Against all Alternatives

Consider the problem of testing the isotonic of several p-variate normal mean vectors against all alternatives. 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. In the present paper, a test statistic is proposed for this problem of testing. A reformulation of the test statistic is given based on the orthogonal projections on the closed convex cones and then the upper bound for p-value of the test statistic is computed.

Exact tests of the superiority under the Poisson distribution

We propose two exact p-values of two commonly-used test statistics for testing the superiority under Poisson populations. We show that, the computationally-intensive confidence-set p-value involves at most a supremum search over a closed interval of a single argument. On the other hand, the estimated p-value has adequate performances empirically.