PGA: power calculator for case-control genetic association analyses

<p>Abstract</p> <p>Background</p> <p>Statistical power calculations inform the design and interpretation of genetic association studies, but few programs are tailored to case-control studies of single nucleotide polymorphisms (SNPs) in unrelated subjects.</p> <p>Results</p> <p>We have developed the "Power for Genetic Association analyses" (PGA) package which comprises algorithms and graphical user interfaces for sample size and minimum detectable risk calculations using SNP or haplotype effects under different genetic models and study constrains. The software accounts for linkage disequilibrium and statistical multiple comparisons. The results are presented in graphs or tables and can be printed or exported in standard file formats.</p> <p>Conclusion</p> <p>PGA is user friendly software that can facilitate decision making for association studies of candidate genes, fine-mapping studies, and whole-genome scans. Stand-alone executable files and a Matlab toolbox are available for download at: <url>http://dceg.cancer.gov/bb/tools/pga</url></p

Design Considerations for Massively Parallel Sequencing Studies of Complex Human Disease

Massively Parallel Sequencing (MPS) allows sequencing of entire exomes and genomes to now be done at reasonable cost, and its utility for identifying genes responsible for rare Mendelian disorders has been demonstrated. However, for a complex disease, study designs need to accommodate substantial degrees of locus, allelic, and phenotypic heterogeneity, as well as complex relationships between genotype and phenotype. Such considerations include careful selection of samples for sequencing and a well-developed strategy for identifying the few “true” disease susceptibility genes from among the many irrelevant genes that will be found to harbor rare variants. To examine these issues we have performed simulation-based analyses in order to compare several strategies for MPS sequencing in complex disease. Factors examined include genetic architecture, sample size, number and relationship of individuals selected for sequencing, and a variety of filters based on variant type, multiple observations of genes and concordance of genetic variants within pedigrees. A two-stage design was assumed where genes from the MPS analysis of high-risk families are evaluated in a secondary screening phase of a larger set of probands with more modest family histories. Designs were evaluated using a cost function that assumes the cost of sequencing the whole exome is 400 times that of sequencing a single candidate gene. Results indicate that while requiring variants to be identified in multiple pedigrees and/or in multiple individuals in the same pedigree are effective strategies for reducing false positives, there is a danger of over-filtering so that most true susceptibility genes are missed. In most cases, sequencing more than two individuals per pedigree results in reduced power without any benefit in terms of reduced overall cost. Further, our results suggest that although no single strategy is optimal, simulations can provide important guidelines for study design

Complications of childbirth and maternal deaths in Kinshasa hospitals: testimonies from women and their families

<p>Abstract</p> <p>Background</p> <p>Maternal mortality in Kinshasa is high despite near universal availability of antenatal care and hospital delivery. Possible explanations are poor-quality care and by delays in the uptake of care. There is, however, little information on the circumstances surrounding maternal deaths. This study describes and compares the circumstances of survivors and non survivors of severe obstetric complications.</p> <p>Method</p> <p>Semi structured interviews with 208 women who survived their obstetric complication and with the families of 110 women who died were conducted at home by three experienced nurses under the supervision of EK. All the cases were identified from twelve referral hospitals in Kinshasa after admission for a serious acute obstetric complication. Transcriptions of interviews were analysed with N-Vivo 2.0 and some categories were exported to SPSS 14.0 for further quantitative analysis.</p> <p>Results</p> <p>Testimonies showed that despite attendance at antenatal care, some women were not aware of or minimized danger signs and did not seek appropriate care. Cost was a problem; 5 deceased and 4 surviving women tried to avoid an expensive caesarean section by delivering in a health centre, although they knew the risk. The majority of surviving mothers (for whom the length of stay was known) had the caesarean section on the day of admission while only about a third of those who died did so. Ten women died before the required caesarean section or blood transfusion could take place because they did not bring the money in time. Negligence and lack of staff competence contributed to the poor quality of care. Interviews revealed that patients and their families were aware of the problem, but often powerless to do anything about it.</p> <p>Conclusion</p> <p>Our findings suggest that women with serious obstetric complications have a greater chance of survival in Kinshasa if they have cash, go directly to a functioning referral hospital and have some leverage when dealing with health care staff</p

Swiss residents' arguments for and against a career in medicine

BACKGROUND: In some Western countries, the medical profession is continuously losing prestige, doctors are claiming of high demands, low rewards, and difficult structural working conditions. This study aimed to investigate the arguments given by Swiss residents for and against a career in medicine. METHODS: As part of a prospective cohort study of Swiss medical school graduates on career development, 567 fourth-year residents were asked to answer the free-response item of what arguments there still were in favour of or against a career in medicine. They also indicated whether they would choose the medical profession all over again (yes/no). The statements were transcribed, content categories inductively formulated, and their descriptions written down in a code manual. Arguments were encoded according to the code manual and assigned to eight content categories (Mayring's content analysis). Frequency distributions were given for categories and tested with Chi(2)-tests for differences in gender, speciality fields, and whether or not the respondent would again choose a career in medicine. RESULTS: The 567 participants made 1,640 statements in favour of and 1,703 statements against a career in medicine. The content analysis of the residents' answers yielded eight categories with arguments both for and against a career in medicine. Of all "statements for" responses, 70% fell into the two top-ranking categories of Personal experiences in day-to-day working life (41.2%) and Interpersonal experiences in professional relationships (28.8%). The top-ranking category of the "statements against" arguments was General work-related structural conditions (32%), followed by Social prestige and health-policy aspects (21%). Main arguments in favour of a career in medicine were interdisciplinary challenge, combination of basic sciences and interpersonal concerns, helping suffering people, guarantee of a secure job; arguments against comprised high workload, time pressure, emotional stress, poorly structured continuing education, increasing bureaucracy, work-life imbalance, low income, and decreasing social prestige. The statements revealed few differences depending on gender, medical field, and attitude towards choosing the medical profession again; one out of five young doctors would not do so. CONCLUSION: Residents' chief complaint is deteriorating structural working conditions, including unfavourable work-life balance. Making medicine an attractive profession again will require sustainable changes in health-policy framework and social reward

Assessment of explanatory models of mental illness: effects of patient and interviewer characteristics

Background: Explanatory models (EMs) refer to patients’ causal attributions of illness and have been shown to affect treatment preference and outcome. Reliable and valid assessment of EMs may be hindered by interviewer and respondent disparities on certain demographic characteristics, such as ethnicity. The present study examined (a) whether ethnic minority patients reported different EMs to ethnically similar interviewers in comparison with those with a different ethnicity, and (b) whether this effect was related to respondents’ social desirability, the perceived rapport with the interviewer and level of uncertainty toward their EMs. Methods: A total of 55 patients of Turkish and Moroccan origins with mood and anxiety disorders were randomly assigned to ethnically similar or dissimilar interviewers. EMs were assessed, using a semi-structured interview, across 11 different categories of causes. Results: Participants who were interviewed by an ethnically similar interviewer perceived interpersonal, victimization and religious/mystical causes as more important, whereas interviews by ethnically dissimilar interviewers generated higher scores on medical causes. These effects were not mediated by the perceived rapport with the interviewer, and social desirability had a modest impact on the results. Higher uncertainty among participants toward medical and religious/mystical causes seemed to be associated with greater adjustment in the report of these EMs. Conclusion: The findings have significant implications for interviewer selection in epidemiological research and clinical practice

Crystallisation route map

A route map for the assessment of crystallisation processes is presented. A theoretical background on solubility, meta-stable zone width, nucleation and crystal growth kinetics is presented with practical examples. The concepts of crystallisation hydrodynamics and the application of population balances and computational fluid dynamics for modelling crystallisation processes and their scaling up are also covered

Doom and Boom on a Resilient Reef: Climate Change, Algal Overgrowth and Coral Recovery

Background: Coral reefs around the world are experiencing large-scale degradation, largely due to global climate change, overfishing, diseases and eutrophication. Climate change models suggest increasing frequency and severity of warming-induced coral bleaching events, with consequent increases in coral mortality and algal overgrowth. Critically, the recovery of damaged reefs will depend on the reversibility of seaweed blooms, generally considered to depend on grazing of the seaweed, and replenishment of corals by larvae that successfully recruit to damaged reefs. These processes usually take years to decades to bring a reef back to coral dominance

Zebrafish Kidney Phagocytes Utilize Macropinocytosis and Ca2+-Dependent Endocytic Mechanisms

Background: The innate immune response constitutes the first line of defense against invading pathogens and consists of a variety of immune defense mechanisms including active endocytosis by macrophages and granulocytes. Endocytosis can be used as a reliable measure of selective and non-selective mechanisms of antigen uptake in the early phase of an immune response. Numerous assays have been developed to measure this response in a variety of mammalian and fish species. The small size of the zebrafish has prevented the large-scale collection of monocytes/macrophages and granulocytes for these endocytic assays. Methodology/Principal Findings: Pooled zebrafish kidney hematopoietic tissues were used as a source of phagocytic cells for flow-cytometry based endocytic assays. FITC-Dextran, Lucifer Yellow and FITC-Edwardsiella ictaluri were used to evaluate selective and non-selective mechanisms of uptake in zebrafish phagocytes. Conclusions/Significance: Zebrafish kidney phagocytes characterized as monocytes/macrophages, neutrophils and lymphocytes utilize macropinocytosis and Ca 2+-dependant endocytosis mechanisms of antigen uptake. These cells do not appear to utilize a mannose receptor. Heat-killed Edwardsiella ictaluri induces cytoskeletal interactions for internalization in zebrafish kidney monocytes/macrophages and granulocytes. The proposed method is easy to implement and should prove especially useful in immunological, toxicological and epidemiological research