Sample size requirements to detect the effect of a group of genetic variants in case-control studies

<p>Abstract</p> <p>Background</p> <p>Because common diseases are caused by complex interactions among many genetic variants along with environmental risk factors, very large sample sizes are usually needed to detect such effects in case-control studies. Nevertheless, many genetic variants act in well defined biologic systems or metabolic pathways. Therefore, a reasonable first step may be to detect the effect of a group of genetic variants before assessing specific variants.</p> <p>Methods</p> <p>We present a simple method for determining approximate sample sizes required to detect the average joint effect of a group of genetic variants in a case-control study for multiplicative models.</p> <p>Results</p> <p>For a range of reasonable numbers of genetic variants, the sample size requirements for the test statistic proposed here are generally not larger than those needed for assessing marginal effects of individual variants and actually decline with increasing number of genetic variants in many situations considered in the group.</p> <p>Conclusion</p> <p>When a significant effect of the group of genetic variants is detected, subsequent multiple tests could be conducted to detect which individual genetic variants and their combinations are associated with disease risk. When testing for an effect size in a group of genetic variants, one can use our global test described in this paper, because the sample size required to detect an effect size in the group is comparatively small. Our method could be viewed as a screening tool for assessing groups of genetic variants involved in pathogenesis and etiology of common complex human diseases.</p

Study protocol: differential effects of diet and physical activity based interventions in pregnancy on maternal and fetal outcomes--individual patient data (IPD) meta-analysis and health economic evaluation.

© 2014 Ruifrok et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BACKGROUND: Pregnant women who gain excess weight are at risk of complications during pregnancy and in the long term. Interventions based on diet and physical activity minimise gestational weight gain with varied effect on clinical outcomes. The effect of interventions on varied groups of women based on body mass index, age, ethnicity, socioeconomic status, parity, and underlying medical conditions is not clear. Our individual patient data (IPD) meta-analysis of randomised trials will assess the differential effect of diet- and physical activity-based interventions on maternal weight gain and pregnancy outcomes in clinically relevant subgroups of women. METHODS/DESIGN: Randomised trials on diet and physical activity in pregnancy will be identified by searching the following databases: MEDLINE, EMBASE, BIOSIS, LILACS, Pascal, Science Citation Index, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database. Primary researchers of the identified trials are invited to join the International Weight Management in Pregnancy Collaborative Network and share their individual patient data. We will reanalyse each study separately and confirm the findings with the original authors. Then, for each intervention type and outcome, we will perform as appropriate either a one-step or a two-step IPD meta-analysis to obtain summary estimates of effects and 95% confidence intervals, for all women combined and for each subgroup of interest. The primary outcomes are gestational weight gain and composite adverse maternal and fetal outcomes. The difference in effects between subgroups will be estimated and between-study heterogeneity suitably quantified and explored. The potential for publication bias and availability bias in the IPD obtained will be investigated. We will conduct a model-based economic evaluation to assess the cost effectiveness of the interventions to manage weight gain in pregnancy and undertake a value of information analysis to inform future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2013: CRD42013003804.This study was funded by the National Institute for Health Research (NIHR) HTA (Health Technology Assessment) UK programme 12/01

The Surgical Infection Society revised guidelines on the management of intra-abdominal infection

Background: Previous evidence-based guidelines on the management of intra-abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the time the most recent guideline was released, the plan was to update the guideline every five years to ensure the timeliness and appropriateness of the recommendations. Methods: Based on the previous guidelines, the task force outlined a number of topics related to the treatment of patients with IAI and then developed key questions on these various topics. All questions were approached using general and specific literature searches, focusing on articles and other information published since 2008. These publications and additional materials published before 2008 were reviewed by the task force as a whole or by individual subgroups as to relevance to individual questions. Recommendations were developed by a process of iterative consensus, with all task force members voting to accept or reject each recommendation. Grading was based on the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) system; the quality of the evidence was graded as high, moderate, or weak, and the strength of the recommendation was graded as strong or weak. Review of the document was performed by members of the SIS who were not on the task force. After responses were made to all critiques, the document was approved as an official guideline of the SIS by the Executive Council. Results: This guideline summarizes the current recommendations developed by the task force on the treatment of patients who have IAI. Evidence-based recommendations have been made regarding risk assessment in individual patients; source control; the timing, selection, and duration of antimicrobial therapy; and suggested approaches to patients who fail initial therapy. Additional recommendations related to the treatment of pediatric patients with IAI have been included. Summary: The current recommendations of the SIS regarding the treatment of patients with IAI are provided in this guideline

Genetic educational needs and the role of genetics in primary care: a focus group study with multiple perspectives

Contains fulltext : 96953.pdf (publisher's version ) (Open Access)BACKGROUND: Available evidence suggests that improvements in genetics education are needed to prepare primary care providers for the impact of ongoing rapid advances in genomics. Postgraduate (physician training) and master (midwifery training) programmes in primary care and public health are failing to meet these perceived educational needs. The aim of this study was to explore the role of genetics in primary care (i.e. family medicine and midwifery care) and the need for education in this area as perceived by primary care providers, patient advocacy groups and clinical genetics professionals. METHODS: Forty-four participants took part in three types of focus groups: mono-disciplinary groups of general practitioners and midwives, respectively and multidisciplinary groups composed of a diverse set of experts. The focus group sessions were audio-taped, transcribed verbatim and analysed using content analysis. Recurrent themes were identified. RESULTS: Four themes emerged regarding the educational needs and the role of genetics in primary care: (1) genetics knowledge, (2) family history, (3) ethical dilemmas and psychosocial effects in relation to genetics and (4) insight into the organisation and role of clinical genetics services. These themes reflect a shift in the role of genetics in primary care with implications for education. Although all focus group participants acknowledged the importance of genetics education, general practitioners felt this need more urgently than midwives and more strongly emphasized their perceived knowledge deficiencies. CONCLUSION: The responsibilities of primary care providers with regard to genetics require further study. The results of this study will help to develop effective genetics education strategies to improve primary care providers' competencies in this area. More research into the educational priorities in genetics is needed to design courses that are suitable for postgraduate and master programmes for general practitioners and midwives

Allogeneic cord blood regulatory T cells decrease dsDNA antibody and improve albuminuria in systemic lupus erythematosus

BackgroundLupus nephritis (LN) constitutes the most severe organ manifestations of systemic lupus erythematosus (SLE), where pathogenic T cells have been identified to play an essential role in ‘helping’ B cells to make autoantibodies and produce inflammatory cytokines that drive kidney injury in SLE. Regulatory T cells (Tregs), responsible for decreasing inflammation, are defective and decreased in SLE and have been associated with disease progression. We hypothesize that treatment with allogeneic, healthy Tregs derived from umbilical cord blood (UCB) may arrest such an inflammatory process and protect against kidney damage.MethodsUCB-Tregs function was examined by their ability to suppress CellTrace Violet-labeled SLE peripheral blood mononuclear cells (PBMCs) or healthy donor (HD) conventional T cells (Tcons); and by inhibiting secretion of inflammatory cytokines by SLE PBMCs. Humanized SLE model was established where female Rag2-/-γc-/- mice were transplanted with 3 × 106 human SLE-PBMCs by intravenous injection on day 0, followed by single or multiple injection of UCB-Tregs to understand their impact on disease development. Mice PB was assessed weekly by flow cytometry. Phenotypic analysis of isolated cells from mouse PB, lung, spleen, liver and kidney was performed by flow cytometry. Kidney damage was assessed by quantifying urinary albumin and creatinine secretion. Systemic disease was evaluated by anti-dsDNA IgG Ab analysis as well as immunohistochemistry analysis of organs. Systemic inflammation was determined by measuring cytokine levels.ResultsIn vitro, UCB-Tregs are able to suppress HD Tcons and pathogenic SLE-PBMCs to a similar extent. UCB-Tregs decrease secretion of several inflammatory cytokines including IFN-γ, IP-10, TNF-α, IL-6, IL-17A, and sCD40L by SLE PBMCs in a time-dependent manner, with a corresponding increase in secretion of suppressor cytokine, IL-10. In vivo, single or multiple doses of UCB-Tregs led to a decrease in CD8+ T effector cells in different organs and a decrease in circulating inflammatory cytokines. Improvement in skin inflammation and loss of hair; and resolution of CD3+, CD8+, CD20+ and Ki67+ SLE-PBMC infiltration was observed in UCB-Treg recipients with a corresponding decrease in plasma anti-double stranded DNA IgG antibody levels and improved albuminuria.ConclusionsUCB-Tregs can decrease inflammatory burden in SLE, reduce auto-antibody production and resolve end organ damage especially, improve kidney function. Adoptive therapy with UCB-Tregs should be explored for treatment of lupus nephritis in the clinical setting

Confirmation of the Secondary Constraint and Absence of Ghost in Massive Gravity and Bimetric Gravity

In massive gravity and in bimetric theories of gravity, two constraints are needed to eliminate the two phase-space degrees of freedom of the Boulware-Deser ghost. For recently proposed non-linear theories, a Hamiltonian constraint has been shown to exist and an associated secondary constraint was argued to arise as well. In this paper we explicitly demonstrate the existence of the secondary constraint. Thus the Boulware-Deser ghost is completely absent from these non-linear massive gravity theories and from the corresponding bimetric theories.Comment: 15 page

GAPscreener: An automatic tool for screening human genetic association literature in PubMed using the support vector machine technique

<p>Abstract</p> <p>Background</p> <p>Synthesis of data from published human genetic association studies is a critical step in the translation of human genome discoveries into health applications. Although genetic association studies account for a substantial proportion of the abstracts in PubMed, identifying them with standard queries is not always accurate or efficient. Further automating the literature-screening process can reduce the burden of a labor-intensive and time-consuming traditional literature search. The Support Vector Machine (SVM), a well-established machine learning technique, has been successful in classifying text, including biomedical literature. The GAPscreener, a free SVM-based software tool, can be used to assist in screening PubMed abstracts for human genetic association studies.</p> <p>Results</p> <p>The data source for this research was the HuGE Navigator, formerly known as the HuGE Pub Lit database. Weighted SVM feature selection based on a keyword list obtained by the two-way z score method demonstrated the best screening performance, achieving 97.5% recall, 98.3% specificity and 31.9% precision in performance testing. Compared with the traditional screening process based on a complex PubMed query, the SVM tool reduced by about 90% the number of abstracts requiring individual review by the database curator. The tool also ascertained 47 articles that were missed by the traditional literature screening process during the 4-week test period. We examined the literature on genetic associations with preterm birth as an example. Compared with the traditional, manual process, the GAPscreener both reduced effort and improved accuracy.</p> <p>Conclusion</p> <p>GAPscreener is the first free SVM-based application available for screening the human genetic association literature in PubMed with high recall and specificity. The user-friendly graphical user interface makes this a practical, stand-alone application. The software can be downloaded at no charge.</p

Human CD34+ CD133+ Hematopoietic Stem Cells Cultured with Growth Factors Including Angptl5 Efficiently Engraft Adult NOD-SCID Il2rγ−/− (NSG) Mice

Increasing demand for human hematopoietic stem cells (HSCs) in clinical and research applications necessitates expansion of HSCs in vitro. Before these cells can be used they must be carefully evaluated to assess their stem cell activity. Here, we expanded cord blood CD34+ CD133+ cells in a defined medium containing angiopoietin like 5 and insulin-like growth factor binding protein 2 and evaluated the cells for stem cell activity in NOD-SCID Il2rg−/− (NSG) mice by multi-lineage engraftment, long term reconstitution, limiting dilution and serial reconstitution. The phenotype of expanded cells was characterized by flow cytometry during the course of expansion and following engraftment in mice. We show that the SCID repopulating activity resides in the CD34+ CD133+ fraction of expanded cells and that CD34+ CD133+ cell number correlates with SCID repopulating activity before and after culture. The expanded cells mediate long-term hematopoiesis and serial reconstitution in NSG mice. Furthermore, they efficiently reconstitute not only neonate but also adult NSG recipients, generating human blood cell populations similar to those reported in mice reconstituted with uncultured human HSCs. These findings suggest an expansion of long term HSCs in our culture and show that expression of CD34 and CD133 serves as a marker for HSC activity in human cord blood cell cultures. The ability to expand human HSCs in vitro should facilitate clinical use of HSCs and large-scale construction of humanized mice from the same donor for research applications.Singapore-MIT Alliance for Research and Technology ( Infectious Diseases research grant

CD36 Participates in PrP106–126-Induced Activation of Microglia

Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The molecular mechanisms that underlie prion-induced microglial activation are not very well understood. In the present study, we investigated the role of the class B scavenger receptor CD36 in microglial activation induced by neurotoxic prion protein (PrP) fragment 106–126 (PrP106–126). We first examined the time course of CD36 mRNA expression upon exposure to PrP106–126 in BV2 microglia. We then analyzed different parameters of microglial activation in PrP106–126-treated cells in the presence or not of anti-CD36 monoclonal antibody (mAb). The cells were first incubated for 1 h with CD36 monoclonal antibody to block the CD36 receptor, and were then treated with neurotoxic prion peptides PrP106–126. The results showed that PrP106–126 treatment led to a rapid yet transitory increase in the mRNA expression of CD36, upregulated mRNA and protein levels of proinflammatory cytokines (IL-1β, IL-6 and TNF-α), increased iNOS expression and nitric oxide (NO) production, stimulated the activation of NF-κB and caspase-1, and elevated Fyn activity. The blockade of CD36 had no effect on PrP106–126-stimulated NF-κB activation and TNF-α protein release, abrogated the PrP106–126-induced iNOS stimulation, downregulated IL-1β and IL-6 expression at both mRNA and protein levels as well as TNF-α mRNA expression, decreased NO production and Fyn phosphorylation, reduced caspase-1 cleavage induced by moderate PrP106–126 –treatment, but had no effect on caspase-1 activation after treatment with a high concentration of PrP106–126. Together, these results suggest that CD36 is involved in PrP106–126-induced microglial activation and that the participation of CD36 in the interaction between PrP106–126 and microglia may be mediated by Src tyrosine kinases. Our findings provide new insights into the mechanisms underlying the activation of microglia by neurotoxic prion peptides and open perspectives for new therapeutic strategies for prion diseases by modulation of CD36 signaling