Application of Two-Part Statistics for Comparison of Sequence Variant Counts

Investigation of microbial communities, particularly human associated communities, is significantly enhanced by the vast amounts of sequence data produced by high throughput sequencing technologies. However, these data create high-dimensional complex data sets that consist of a large proportion of zeros, non-negative skewed counts, and frequently, limited number of samples. These features distinguish sequence data from other forms of high-dimensional data, and are not adequately addressed by statistical approaches in common use. Ultimately, medical studies may identify targeted interventions or treatments, but lack of analytic tools for feature selection and identification of taxa responsible for differences between groups, is hindering advancement. The objective of this paper is to examine the application of a two-part statistic to identify taxa that differ between two groups. The advantages of the two-part statistic over common statistical tests applied to sequence count datasets are discussed. Results from the t-test, the Wilcoxon test, and the two-part test are compared using sequence counts from microbial ecology studies in cystic fibrosis and from cenote samples. We show superior performance of the two-part statistic for analysis of sequence data. The improved performance in microbial ecology studies was independent of study type and sequence technology used

Trial protocol OPPTIMUM : does progesterone prophylaxis for the prevention of preterm labour improve outcome?

Background Preterm birth is a global problem, with a prevalence of 8 to 12% depending on location. Several large trials and systematic reviews have shown progestogens to be effective in preventing or delaying preterm birth in selected high risk women with a singleton pregnancy (including those with a short cervix or previous preterm birth). Although an improvement in short term neonatal outcomes has been shown in some trials these have not consistently been confirmed in meta-analyses. Additionally data on longer term outcomes is limited to a single trial where no difference in outcomes was demonstrated at four years of age of the child, despite those in the “progesterone” group having a lower incidence of preterm birth. Methods/Design The OPPTIMUM study is a double blind randomized placebo controlled trial to determine whether progesterone prophylaxis to prevent preterm birth has long term neonatal or infant benefit. Specifically it will study whether, in women with singleton pregnancy and at high risk of preterm labour, prophylactic vaginal natural progesterone, 200 mg daily from 22 – 34 weeks gestation, compared to placebo, improves obstetric outcome by lengthening pregnancy thus reducing the incidence of preterm delivery (before 34 weeks), improves neonatal outcome by reducing a composite of death and major morbidity, and leads to improved childhood cognitive and neurosensory outcomes at two years of age. Recruitment began in 2009 and is scheduled to close in Spring 2013. As of May 2012, over 800 women had been randomized in 60 sites. Discussion OPPTIMUM will provide further evidence on the effectiveness of vaginal progesterone for prevention of preterm birth and improvement of neonatal outcomes in selected groups of women with singleton pregnancy at high risk of preterm birth. Additionally it will determine whether any reduction in the incidence of preterm birth is accompanied by improved childhood outcome

Malaria vaccine efficacy: the difficulty of detecting and diagnosing malaria

New sources of funding have revitalized efforts to control malaria. An effective vaccine would be a tremendous asset in the fight against this devastating disease and increasing financial and scientific resources are being invested to develop one. A few candidates have been tested in Phase I and II clinical trials, and several others are poised to begin trials soon. Some studies have been promising, and others disappointing. It is difficult to compare the results of these clinical trials; even independent trials of the same vaccine give highly discrepant results. One major obstacle in evaluating malaria vaccines is the difficulty of diagnosing clinical malaria. This analysis evaluates the impact of diagnostic error, particularly that introduced by microscopy, on the outcome of efficacy trials of malaria vaccines and make recommendations for improving future trials

Impact of the introduction of pneumococcal conjugate vaccine on immunization coverage among infants

Background The introduction of pneumococcal conjugate vaccine (PCV) to the U.S. recommended childhood immunization schedule in the year 2000 added three injections to the number of vaccinations a child is expected to receive during the first year of life. Surveys have suggested that the addition of PCV has led some immunization providers to move other routine childhood vaccinations to later ages, which could increase the possibility of missing these vaccines. The purpose of this study was to evaluate whether introduction of PCV affected immunization coverage for recommended childhood vaccinations among 13-month olds in four large provider groups. Methods In this retrospective cohort study, we analyzed computerized data on vaccinations for 33,319 children in four large provider groups before and after the introduction of PCV. The primary outcome was whether the child was up to date for all non-PCV recommended vaccinations at 13 months of age. Logistic regression was used to evaluate the association between PCV introduction and the primary outcome. The secondary outcome was the number of days spent underimmunized by 13 months. The association between PCV introduction and the secondary outcome was evaluated using a two-part modelling approach using logistic and negative binomial regression. Results Overall, 93% of children were up-to-date at 13 months, and 70% received all non-PCV vaccinations without any delay. Among the entire study population, immunization coverage was maintained or slightly increased from the pre-PCV to post-PCV periods. After multivariate adjustment, children born after PCV entered routine use were less likely to be up-to-date at 13 months in one provider group (Group C: OR = 0.5; 95% CI: 0.3 – 0.8) and were less likely to have received all vaccine doses without any delay in two Groups (Group B: OR = 0.4, 95% CI: 0.3 – 0.6; Group C: OR = 0.5, 95% CI: 0.4 – 0.7). This represented 3% fewer children in Group C who were up-to-date and 14% (Group C) to 16% (Group B) fewer children who spent no time underimmunized at 13 months after PCV entered routine use compared to the pre-PCV baseline. Some disruptions in immunization delivery were also observed concurrent with temporary recommendations to suspend the birth dose of hepatitis B vaccine, preceding the introduction of PCV. Conclusion These findings suggest that the introduction of PCV did not harm overall immunization coverage rates in populations with good access to primary care. However, we did observe some disruptions in the timely delivery of other vaccines coincident with the introduction of PCV and the suspension of the birth dose of hepatitis B vaccine. This study highlights the need for continued vigilance in coming years as the U.S. introduces new childhood vaccines and policies that may change the timing of existing vaccines

Comparative reliability and diagnostic performance of conventional 3T magnetic resonance imaging and 1.5T magnetic resonance arthrography for the evaluation of internal derangement of the hip

Objective; To compare the diagnostic accuracy of conventional 3T MRI against 1.5T MR arthrography (MRA) in patients with clinical femoroacetabular impingement (FAI). Methods; Sixty-eight consecutive patients with clinical FAI underwent both 1.5T MRA and 3T MRI. Imaging was prospectively analysed by two musculoskeletal radiologists, blinded to patient outcomes and scored for internal derangement including labral and cartilage abnormality. Interobserver variation was assessed by kappa analysis. Thirty-nine patients subsequently underwent hip arthroscopy and surgical results and radiology findings were analysed. Results; Both readers had higher sensitivities for detecting labral tears with 3T MRI compared to 1.5T MRA (not statistically significant p=0.07). For acetabular cartilage defect both readers had higher statistically significant sensitivities using 3T MRI compared to 1.5T MRA (p=0.02). Both readers had a slightly higher sensitivity for detecting delamination with 1.5T MRA compared to 3T MRI, but these differences were not statistically significant (p=0.66). Interobserver agreement was substantial to perfect agreement for all parameters except the identification of delamination (3T MRI showed moderate agreement and 1.5T MRA substantial agreement). Conclusion; Conventional 3T MRI may be at least equivalent to 1.5T MRA in detecting acetabular labrum and possibly superior to 1.5T MRA in detecting cartilage defects in patients with suspected FAI

Nasal Bone Shape Is under Complex Epistatic Genetic Control in Mouse Interspecific Recombinant Congenic Strains

Genetic determinism of cranial morphology in the mouse is still largely unknown, despite the localization of putative QTLs and the identification of genes associated with Mendelian skull malformations. To approach the dissection of this multigenic control, we have used a set of interspecific recombinant congenic strains (IRCS) produced between C57BL/6 and mice of the distant species Mus spretus (SEG/Pas). Each strain has inherited 1.3% of its genome from SEG/Pas under the form of few, small-sized, chromosomal segments.The shape of the nasal bone was studied using outline analysis combined with Fourier descriptors, and differential features were identified between IRCS BcG-66H and C57BL/6. An F2 cross between BcG-66H and C57BL/6 revealed that, out of the three SEG/Pas-derived chromosomal regions present in BcG-66H, two were involved. Segments on chromosomes 1 (∼32 Mb) and 18 (∼13 Mb) showed additive effect on nasal bone shape. The three chromosomal regions present in BcG-66H were isolated in congenic strains to study their individual effect. Epistatic interactions were assessed in bicongenic strains.Our results show that, besides a strong individual effect, the QTL on chromosome 1 interacts with genes on chromosomes 13 and 18. This study demonstrates that nasal bone shape is under complex genetic control but can be efficiently dissected in the mouse using appropriate genetic tools and shape descriptors

Bias adjustment and ensemble recalibration methods for seasonal forecasting: a comprehensive intercomparison using the C3S dataset

This work presents a comprehensive intercomparison of diferent alternatives for the calibration of seasonal forecasts, ranging from simple bias adjustment (BA)-e.g. quantile mapping-to more sophisticated ensemble recalibration (RC) methods- e.g. non-homogeneous Gaussian regression, which build on the temporal correspondence between the climate model and the corresponding observations to generate reliable predictions. To be as critical as possible, we validate the raw model and the calibrated forecasts in terms of a number of metrics which take into account diferent aspects of forecast quality (association, accuracy, discrimination and reliability). We focus on one-month lead forecasts of precipitation and temperature from four state-of-the-art seasonal forecasting systems, three of them included in the Copernicus Climate Change Service dataset (ECMWF-SEAS5, UK Met Ofce-GloSea5 and Météo France-System5) for boreal winter and summer over two illustrative regions with diferent skill characteristics (Europe and Southeast Asia). Our results indicate that both BA and RC methods efectively correct the large raw model biases, which is of paramount importance for users, particularly when directly using the climate model outputs to run impact models, or when computing climate indices depending on absolute values/thresholds. However, except for particular regions and/or seasons (typically with high skill), there is only marginal added value-with respect to the raw model outputs-beyond this bias removal. For those cases, RC methods can outperform BA ones, mostly due to an improvement in reliability. Finally, we also show that whereas an increase in the number of members only modestly afects the results obtained from calibration, longer hindcast periods lead to improved forecast quality, particularly for RC methods.This work has been funded by the C3S activity on Evaluation and Quality Control for seasonal forecasts. JMG was partially supported by the project MULTI-SDM (CGL2015-66583-R, MINECO/FEDER). FJDR was partially funded by the H2020 EUCP project (GA 776613)

Prognostic indicators in adults hospitalized with falciparum malaria in Western Thailand.

Background: Severe malaria remains a major cause of death and morbidity amongst adults in the Asiatic tropics. Methods: A retrospective analysis of the clinical and laboratory data of 988 adult patients, hospitalized with Plasmodium falciparum malaria and prospectively recruited to malaria studies in western Thailand between 1986 and 2002, was performed to assess the factors associated with a fatal outcome. Different severity scores and classifications for defining severe malaria were compared and, using multiple logistic regression, simple models for predicting mortality developed. Results: The proportion of patients fulfilling the WHO 2000 definition of severe malaria was 78.1%, and their mortality was 10%. Mortality in patients given parenteral artesunate or artemether (16/317, 5%) was lower than in those given parenteral quinine (59/442, 13%) (P < 0.001). Models using parameter sets based on WHO 1990, 2000 and Adapted AQ criteria plus blood smear parasite-stage assessment gave the best mortality prediction. A malaria prognostic index (MPI), derived from the dataset using five clinical or laboratory variables gave similar prognostic accuracy. Conclusions: The mortality of severe malaria in adults has fallen and the switch from quinine to artesunate has probably been an important contributor. Prognostic indices based on WHO 2000 definitions, and other simpler indices based on fewer variables, provide clinically useful predictions of outcome in Asian adults with severe malaria

A stable pattern of EEG spectral coherence distinguishes children with autism from neuro-typical controls - a large case control study

<p>Abstract</p> <p>Background</p> <p>The autism rate has recently increased to 1 in 100 children. Genetic studies demonstrate poorly understood complexity. Environmental factors apparently also play a role. Magnetic resonance imaging (MRI) studies demonstrate increased brain sizes and altered connectivity. Electroencephalogram (EEG) coherence studies confirm connectivity changes. However, genetic-, MRI- and/or EEG-based diagnostic tests are not yet available. The varied study results likely reflect methodological and population differences, small samples and, for EEG, lack of attention to group-specific artifact.</p> <p>Methods</p> <p>Of the 1,304 subjects who participated in this study, with ages ranging from 1 to 18 years old and assessed with comparable EEG studies, 463 children were diagnosed with autism spectrum disorder (ASD); 571 children were neuro-typical controls (C). After artifact management, principal components analysis (PCA) identified EEG spectral coherence factors with corresponding loading patterns. The 2- to 12-year-old subsample consisted of 430 ASD- and 554 C-group subjects (n = 984). Discriminant function analysis (DFA) determined the spectral coherence factors' discrimination success for the two groups. Loading patterns on the DFA-selected coherence factors described ASD-specific coherence differences when compared to controls.</p> <p>Results</p> <p>Total sample PCA of coherence data identified 40 factors which explained 50.8% of the total population variance. For the 2- to 12-year-olds, the 40 factors showed highly significant group differences (<it>P </it>< 0.0001). Ten randomly generated split half replications demonstrated high-average classification success (C, 88.5%; ASD, 86.0%). Still higher success was obtained in the more restricted age sub-samples using the jackknifing technique: 2- to 4-year-olds (C, 90.6%; ASD, 98.1%); 4- to 6-year-olds (C, 90.9%; ASD 99.1%); and 6- to 12-year-olds (C, 98.7%; ASD, 93.9%). Coherence loadings demonstrated reduced short-distance and reduced, as well as increased, long-distance coherences for the ASD-groups, when compared to the controls. Average spectral loading per factor was wide (10.1 Hz).</p> <p>Conclusions</p> <p>Classification success suggests a stable coherence loading pattern that differentiates ASD- from C-group subjects. This might constitute an EEG coherence-based phenotype of childhood autism. The predominantly reduced short-distance coherences may indicate poor local network function. The increased long-distance coherences may represent compensatory processes or reduced neural pruning. The wide average spectral range of factor loadings may suggest over-damped neural networks.</p