Establishing an adjusted p-value threshold to control the family-wide type 1 error in genome wide association studies

<p>Abstract</p> <p>Background</p> <p>By assaying hundreds of thousands of single nucleotide polymorphisms, genome wide association studies (GWAS) allow for a powerful, unbiased review of the entire genome to localize common genetic variants that influence health and disease. Although it is widely recognized that some correction for multiple testing is necessary, in order to control the family-wide Type 1 Error in genetic association studies, it is not clear which method to utilize. One simple approach is to perform a Bonferroni correction using all <it>n single nucleotide polymorphisms (</it>SNPs) across the genome; however this approach is highly conservative and would "overcorrect" for SNPs that are not truly independent. Many SNPs fall within regions of strong linkage disequilibrium (LD) ("blocks") and should not be considered "independent".</p> <p>Results</p> <p>We proposed to approximate the number of "independent" SNPs by counting 1 SNP per LD block, plus all SNPs outside of blocks (interblock SNPs). We examined the <it>effective </it>number of independent SNPs for Genome Wide Association Study (GWAS) panels. In the CEPH Utah (CEU) population, by considering the interdependence of SNPs, we could reduce the total number of effective tests within the Affymetrix and Illumina SNP panels from 500,000 and 317,000 to 67,000 and 82,000 "independent" SNPs, respectively. For the Affymetrix 500 K and Illumina 317 K GWAS SNP panels we recommend using 10^-5, 10^-7and 10^-8and for the Phase II HapMap CEPH Utah and Yoruba populations we recommend using 10^-6, 10^-7and 10^-9as "suggestive", "significant" and "highly significant" p-value thresholds to properly control the family-wide Type 1 error.</p> <p>Conclusion</p> <p>By approximating the effective number of independent SNPs across the genome we are able to 'correct' for a more accurate number of tests and therefore develop 'LD adjusted' Bonferroni corrected p-value thresholds that account for the interdepdendence of SNPs on well-utilized commercially available SNP "chips". These thresholds will serve as guides to researchers trying to decide which regions of the genome should be studied further.</p

The effect of ozone on progression or regression of artificial caries-like enamel lesions in vitro

Objective: This study investigated the effect of ozone on the progression or regression of artificial caries-like lesions on enamel following pH cycling conditions in vitro. Methods: A randomized, single blind, four legs design was used. 20 full thickness enamel slabs were allocated to each of the four groups which were: Fluoride free toothpaste (control); ozone alone; Reductant/Patient Kit alone and a combination of both ozone/Reductant/Patient Kit. Artificial lesions were created and subjected to the pH cycling regime for a 14 days period. Assessments were carried out before and after the pH cycling on the slabs using the microhardness testing and Quantitative Light-induced Fluorescence (QLF). Results: Statistical significant difference were found in the percentage change of enamel microhardness before and after pH cycling between ozone/Reductant/Patient Kit group and all the other three groups of the study, as well as between Reductant/Patient Kit group and control. There was a statistical significant difference in the change of size and severity of the lesion (ΔQ) between all the three regimes tested and the control with a trend favouring ozone/Reductant/Patient Kit group. Conclusions: In our model, it appeared that ozone treatment alone is not effective in protecting the enamel against demineralisation or promoting remineralisation, unless combined with the Reductant/Patient Kit, which contain high levels of fluoride

Improving the Care Pathway for Women who Request Caesarean Section: An Experience-Based Co-Design Study

Background Maternal request for Caesarean section is controversial and yet the NICE Caesarean section Guideline recommends that that if this is requested, following discussion of the risks and benefits, women should be supported in their choice. There was a desire to improve the pathway at Birmingham Women’s NHS Foundation Trust. Methods Experience-based co-design methodology uses service user and clinicians experiences collected using qualitative methods to jointly re-design services. Firstly semi-structured interviews were conducted to elicit the views and experiences of health care professionals and women who requested Caesarean section (with and without medical indication). Analysis identified key themes arising from the health care professionals’ interviews and ‘touch points’ (key moments or events related to the experience of care) arising from the interviews with women.. Separate workshops were then held with each group to ensure these resonated and to identify key areas for service improvement. At the first joint workshop a pathway using ‘audio clips’ demonstrating women’s agreed ‘touch points’ prompted discussion and joint working began to change the pathway. A final second workshop was held to agree changes to the pathway. Results Interviews were conducted with health care professionals (n = 22, 10 consultant obstetricians and 12 midwives) and women (n = 15). The women’s ‘touch points’ included repetition of request, delay in the decision for Caesarean section to be made, feeling judged, and that information was poor with similar findings identified from the health care professionals. Joint working resulted in a revised pathway for women who request Caesarean section. Changes to the pathway for women as a result of the work include written information about ‘The way your baby may be born’ which is given to the woman followed by a discussion about mode of birth around the 16 week appointment. If the woman wishes to have a Caesarean section, referral is made to appropriate health care professionals (e.g., Consultant Midwife, counsellor) only if support and information would be useful. If Caesarean section is requested, woman is referred to a consultant obstetrician for an appointment at 20/40, with a decision by 28/40. Recording this in the notes minimises repeated challenge described by women. Final consent and timing of Caesarean section remain as recommended. Conclusion This has resulted in changes to the pathway agreed by a co-design process and which are acceptable to both health care professionals and women. Use of such methodologies should be considered more frequently when implementing service change

The effect of premature extraction of primary teeth on the subsequent need for orthodontic treatment.

Aim: This was primarily to examine the effect of premature extraction of primary teeth (PEPT) on subsequent malocclusion and need for orthodontic treatment in the permanent dentition. The secondary aim was to correlate the effect of PEPT with loss of space in the primary and mixed dentitions. Methods: A predefined protocol was developed and registered prospectively with PROSPERO database. The electronic databases, searched, were MEDLINE, EMBASE, PubMed, and Cochrane Central Register of Controlled Trials. The study designs considered for inclusion were controlled trials, cohort, and case-control studies. Risk of bias was assessed using a validated quality assessment tool. Results: 513 studies were identified. Sixteen studies were included in the systematic review, one study reported on malocclusion, and 15 studies reported on space changes. Narrative synthesis was undertaken owing to the heterogeneity of the included studies. No study examined the effect of PEPT on orthodontic need. Most studies reported on space dimensions used a split-mouth design and were at a high risk of bias. Conclusions: The included literature identified that PEPT led to various features of malocclusion and space loss in the mixed and permanent dentitions. No studies, that met the inclusion criteria, described the effect of PEPT on the subsequent need for orthodontic treatment

On global models for isolated rotating axisymmetric charged bodies; uniqueness of the exterior field

A relatively recent study by Mars and Senovilla provided us with a uniqueness result for the exterior vacuum gravitational field generated by an isolated distribution of matter in axial rotation in equilibrium in General Relativity. The generalisation to exterior electrovacuum gravitational fields, to include charged rotating objects, is presented here.Comment: LaTeX, 21 pages, uses iopart styl

Regenerative Endodontic Therapy in the Management of Nonvital Immature Permanent Teeth: A Systematic Review—Outcome Evaluation and Meta-analysis

Introduction: Although the protocols in previously published studies appeared to be largely similar, there were inadequate evidence-based guidelines to support a single protocol. Using a meta-analysis, this systematic review aimed to summarize and quantitatively evaluate the outcomes for nonvital immature permanent teeth treated using the regenerative endodontic technique (RET) as well as critically appraise the level and quality of evidence of the existing publications. Methods: Risk of bias assessment and level of evidence grading were performed on all included studies. Meta-analyses using a random effects model were performed to combine the results of randomized controlled trials. The pooled success rate for each exposure was estimated for each outcome (event rates with 95% confidence intervals). The outcomes of all included studies were summarized. Results: Success rates for tooth survival and resolution of periapical pathosis were excellent; however, results for apical closure and continued root development were inconsistent. There are few well-reported randomized prospective clinical studies. Reporting of long-term outcomes and late-stage effects was sparse. No study evaluated health economic outcomes and improvements to patients' quality of life. Conclusions: Many knowledge gaps still exist within the studies published. Current published evidence is unable to provide definitive conclusions on the predictability of RET outcomes

Effect of pH on solubility of white Mineral Trioxide Aggregate and Biodentine: An in vitro study

Background. The aim of this study was to evaluate the effect of acidic, neutral and alkaline environments on the solubility of white mineral trioxide aggregate (WMTA) and Biodentine (BD). Methods. Thirty-nine ring molds were randomly divided into three groups of A, B, and C (n = 12) with pH values of 7.4, 4.4 and 10.4, respectively, and an empty mold was used as a control. Each group was further divided into two subgroups (1 and 2) according to the material studied. The samples in groups A, B and C were transferred into synthetic tissue fluid buffered at pH values of 7.4, 4.4 and 10.4, respectively, and kept in an incubator at 37°C with 100% humidity. Daily solubility at 1-, 2-, 5-, 14-, 21-, and 30-day intervals and cumulative solubility up to 5-, 14-, and 30-day intervals were calculated. Statistical analysis was carried out with independent-samples t-test, two-way ANOVA and post hoc Tukey tests using SPSS 18. Statistical significance was set at P<0.05. Results. Both WMTA and BD exhibited the highest solubility in acidic pH with 5.4235±0.1834 and 10.7516±0.0639 mean cumulative solubility values at 30-day interval, respectively. At all exposure times, BD was significantly more soluble than WMTA (P<0.001). Conclusion. Acidic periapical environment jeopardized the solubility of both WMTA and BD, affecting their sealing characteristics in clinical applications like perforation repair procedures and blunderbuss canals

On the perturbation of the group generalized inverse for a class of bounded operators in Banach spaces

En este trabajo se estudia la perturbación de la inversa generalizada grupo en el ámbito de los operadores lineales y acotados sobre un espacio de Banach complejo. Se establecen, en primer lugar, caracterizaciones de los {1,2}-inversos generalizados de operadores perturbados que verifican una condición de no singularidad. Posteriormente se caracteriza la clase de operadores perturbados para los cuales existe el operador inverso grupo y verifican ciertas condiciones geométricas. Se prueba que los operadores perturbados tienen una determinada estructura de matriz 2 por 2 de operadores y se desarrolla una representación para la resolvente de tales matrices de operadores a partir de la cual se obtiene una representación para el operador inverso grupo. Este resultado extiende al contexto de operadores un resultado para matrices por bloques incluido en el libro [Campbell y Meyer, Generalized inverses of Linear Transformations, Dover, 1979] y nos proporciona una herramienta para el análisis de la perturbación. Otras aportaciones son la obtención de xpresiones explícitas para el operador inverso grupo el operador perturbado y su proyección espectral asociada al 0 y la obtención de cotas superiores para el error relativo de la inversa de Drazin y de los proyectores espectrales y un resultado de continuidad de la inversa grupo para operadores en espacios de Banach. Las aportaciones de este trabajo extienden o complementan resultados obtenidos previamente por autores sobre el mismo tema (Djordjevic, Koliha, Rakoèevic) Given a bounded operator A on a Banach space X with Drazin inverse AD and index r, we study the class of group invertible bounded operators B such that I + A(D)(B - A) is invertible and R(B) boolean AND N(A(r)) = {0}. We show that they can be written with respect to the decomposition X = R(A(r))circle plus N(A(r)) as a matrix operator, B = (B-1 B-12 B-21 B21B1-1B12), where B-1 and B-1(2) + B12B21 are invertible. Several characterizations of the perturbed operators are established, extending matrix results. We analyze the perturbation of the Drazin inverse and we provide explicit upper bounds of parallel to B-# - A(D)parallel to and parallel to BB# - A(D)A parallel to. We obtain a result on the continuity of the group inverse for operators on Banach space

β-pyrophosphate: A potential biomaterial for dental applications

Tooth hypersensitivity is a growing problem affecting both the young and ageing population worldwide. Since an effective and permanent solution is not yet available, we propose a new methodology for the restoration of dental enamel using femtosecond lasers and novel calcium phosphate biomaterials. During this procedure the irradiated mineral transforms into a densified layer of acid resistant iron doped β-pyrophosphate, bonded with the surface of eroded enamel. Our aim therefore is to evaluate this densified mineral as a potential replacement material for dental hard tissue. To this end, we have tested the hardness of β-pyrophosphate pellets (sintered at 1000 °C) and its mineral precursor (brushite), the wear rate during simulated tooth-brushing trials and the cytocompatibility of these minerals in powder form. It was found that the hardness of the β-pyrophosphate pellets is comparable with that of dental enamel and significantly higher than dentine while, the brushing trials prove that the wear rate of β-pyrophosphate is much slower than that of natural enamel. Finally, cytotoxicity and genotoxicity tests suggest that iron doped β-pyrophosphate is cytocompatible and therefore could be used in dental applications. Taken together and with the previously reported results on laser irradiation of these materials we conclude that iron doped β-pyrophosphate may be a promising material for restoring acid eroded and worn enamel