Analysis of Case-Control Age-at-Onset Data Using a Modified Case-Cohort Method

Case-control designs are widely used in rare disease studies. In a typical case-control study, data are collected from a sample of all available subjects who have experienced a disease (cases) and a sub-sample of subjects who have not experienced the disease (controls) in a study cohort. Cases are oversampled in case-control studies. Logistic regression is a common tool to estimate the relative risks of the disease with respect to a set of covariates. Very often in such a study, information of ages-at-onset of the disease for all cases and ages at survey of controls are known. Standard logistic regression analysis using age as a covariate is based on a dichotomous outcome and does not efficiently use such age-at-onset (time-to-event) information. We propose to analyze age-at-onset data using a modified case-cohort method by treating the control group as an approximation of a subcohort assuming rare events. We investigate the asymptotic bias of this approximation and show that the asymptotic bias of the proposed estimator is small when the disease rate is low. We evaluate the finite sample performance of the proposed method through a simulation study and illustrate the method using a breast cancer case-control data set. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58567/1/311_ftp.pd

Pattern and determinants of HIV research productivity in sub-Saharan Africa: bibliometric analysis of 1981 to 2009 PubMed papers

<p>Abstract</p> <p>Background</p> <p>Several bibliometric studies have been published on AIDS. The findings obtained from these studies have provided a general picture of the history and growth of AIDS literature. However, factors related to variation in HIV research productivity in sub-Saharan Africa have not been examined. Therefore, this study aims to fill some of the gap in existing research to provide insights into factors associated with HIV research productivity in sub-Saharan Africa.</p> <p>Methods</p> <p>A bibliometric analysis regarding sub-Saharan Africa HIV/AIDS research was conducted in the PubMed database for the period of 1981 to 2009. The numbers of HIV research articles indexed in PubMed was used as surrogate for total HIV research productivity. Series of univariable and multivariable negative binomial regression models were used to explore factors associated with variation in HIV research productivity in sub-Saharan Africa.</p> <p>Results</p> <p>First authors from South Africa, Uganda and Kenya contributed almost half of the total number of HIV articles indexed in PubMed between 1981 and 2009. Uganda, Zimbabwe and Malawi had better records when the total production was adjusted for gross domestic product (GDP). Comoros, the Gambia and Guinea-Bissau were the most productive countries when the total products were normalized by number of people with HIV. There were strong positive and statistically significant correlation between countries number of indexed journal (Pearson correlation r = 0.77, p = .001), number of higher institutions (r = 0.60, p = .001), number of physicians (r = 0.83, p = .001) and absolute numbers of HIV articles.</p> <p>Conclusions</p> <p>HIV research productivity in Africa is highly skewed. To increase HIV research output, total expenditure on health (% of GDP), private expenditure on health, and adult literacy rate may be important factors to address.</p

A method for identifying genetic heterogeneity within phenotypically defined disease subgroups.

Many common diseases show wide phenotypic variation. We present a statistical method for determining whether phenotypically defined subgroups of disease cases represent different genetic architectures, in which disease-associated variants have different effect sizes in two subgroups. Our method models the genome-wide distributions of genetic association statistics with mixture Gaussians. We apply a global test without requiring explicit identification of disease-associated variants, thus maximizing power in comparison to standard variant-by-variant subgroup analysis. Where evidence for genetic subgrouping is found, we present methods for post hoc identification of the contributing genetic variants. We demonstrate the method on a range of simulated and test data sets, for which expected results are already known. We investigate subgroups of individuals with type 1 diabetes (T1D) defined by autoantibody positivity, establishing evidence for differential genetic architecture with positivity for thyroid-peroxidase-specific antibody, driven generally by variants in known T1D-associated genomic regions.We acknowledge the help of the Diabetes and Inflammation Laboratory Data Service for access and quality control procedures on the data sets used in this study. The JDRF/Wellcome Trust Diabetes and Inflammation Laboratory is in receipt of a Wellcome Trust Strategic Award (107212; J.A.T.) and receives funding from the NIHR Cambridge Biomedical Research Centre. J.L. is funded by the NIHR Cambridge Biomedical Research Centre and is on the Wellcome Trust PhD program in Mathematical Genomics and Medicine at the University of Cambridge. C.W. is funded by the MRC (grant MC_UP_1302/5). We thank M. Simmonds, S. Gough, J. Franklyn, and O. Brand for sharing their AITD genetic association data set and all patients with AITD and control subjects for participating in this study. The AITD UK national collection was funded by the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Monoamine oxidase A (MAO-A), a mitochondrial enzyme that degrades monoamines including neurotransmitters, is highly expressed in basal cells of the normal human prostatic epithelium and in poorly differentiated (Gleason grades 4 and 5), aggressive prostate cancer (PCa). Clorgyline, an MAO-A inhibitor, induces secretory differentiation of normal prostate cells. We examined the effects of clorgyline on the transcriptional program of epithelial cells cultured from high grade PCa (E-CA).</p> <p>Methods</p> <p>We systematically assessed gene expression changes induced by clorgyline in E-CA cells using high-density oligonucleotide microarrays. Genes differentially expressed in treated and control cells were identified by Significance Analysis of Microarrays. Expression of genes of interest was validated by quantitative real-time polymerase chain reaction.</p> <p>Results</p> <p>The expression of 156 genes was significantly increased by clorgyline at all time points over the time course of 6 – 96 hr identified by Significance Analysis of Microarrays (SAM). The list is enriched with genes repressed in 7 of 12 oncogenic pathway signatures compiled from the literature. In addition, genes downregulated ≥ 2-fold by clorgyline were significantly enriched with those upregulated by key oncogenes including beta-catenin and ERBB2, indicating an anti-oncogenic effect of clorgyline. Another striking effect of clorgyline was the induction of androgen receptor (AR) and classic AR target genes such as prostate-specific antigen together with other secretory epithelial cell-specific genes, suggesting that clorgyline promotes differentiation of cancer cells. Moreover, clorgyline downregulated EZH2, a critical component of the Polycomb Group (PcG) complex that represses the expression of differentiation-related genes. Indeed, many genes in the PcG repression signature that predicts PCa outcome were upregulated by clorgyline, suggesting that the differentiation-promoting effect of clorgyline may be mediated by its downregulation of EZH2.</p> <p>Conclusion</p> <p>Our results suggest that inhibitors of MAO-A, already in clinical use to treat depression, may have potential application as therapeutic PCa drugs by inhibiting oncogenic pathway activity and promoting differentiation.</p

The ATP-Binding Cassette Proteins of the Deep-Branching Protozoan Parasite Trichomonas vaginalis

The ATP binding cassette (ABC) proteins are a family of membrane transporters and regulatory proteins responsible for diverse and critical cellular process in all organisms. To date, there has been no attempt to investigate this class of proteins in the infectious parasite Trichomonas vaginalis. We have utilized a combination of bioinformatics, gene sequence analysis, gene expression and confocal microscopy to investigate the ABC proteins of T. vaginalis. We demonstrate that, uniquely among eukaryotes, T. vaginalis possesses no intact full-length ABC transporters and has undergone a dramatic expansion of some ABC protein sub-families. Furthermore, we provide preliminary evidence that T. vaginalis is able to read through in-frame stop codons to express ABC transporter components from gene pairs in a head-to-tail orientation. Finally, with confocal microscopy we demonstrate the expression and endoplasmic reticulum localization of a number of T. vaginalis ABC transporters

Post-supereruption recovery at Toba Caldera

Large calderas, or supervolcanoes, are sites of the most catastrophic and hazardous events on Earth, yet the temporal details of post-supereruption activity, or resurgence, remain largely unknown, limiting our ability to understand how supervolcanoes work and address their hazards. Toba Caldera, Indonesia, caused the greatest volcanic catastrophe of the last 100 kyr, climactically erupting ~74 ka. Since the supereruption, Toba has been in a state of resurgence but its magmatic and uplift history has remained unclear. Here we reveal that new 14 C, zircon U-Th crystallization and (U-Th)/He ages show resurgence commenced at 69.7±4.5 ka and continued until at least ~2.7 ka, progressing westward across the caldera, as reflected by post-caldera effusive lava eruptions and uplifted lake sediment. The major stratovolcano north of Toba, Sinabung, shows strong geochemical kinship with Toba, and zircons from recent eruption products suggest Toba's climactic magma reservoir extends beneath Sinabung and is being tapped during eruptions

Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of Human Blood Mononuclear Cells

Newborns and young infants suffer increased infectious morbidity and mortality as compared to older children and adults. Morbidity and mortality due to infection are highest during the first weeks of life, decreasing over several years. Furthermore, most vaccines are not administered around birth, but over the first few years of life. A more complete understanding of the ontogeny of the immune system over the first years of life is thus urgently needed. Here, we applied the most comprehensive analysis focused on the innate immune response following TLR stimulation over the first 2 years of life in the largest such longitudinal cohort studied to-date (35 subjects). We found that innate TLR responses (i) known to support Th17 adaptive immune responses (IL-23, IL-6) peaked around birth and declined over the following 2 years only to increase again by adulthood; (ii) potentially supporting antiviral defense (IFN-α) reached adult level function by 1 year of age; (iii) known to support Th1 type immunity (IL-12p70, IFN-γ) slowly rose from a low at birth but remained far below adult responses even at 2 years of age; (iv) inducing IL-10 production steadily declined from a high around birth to adult levels by 1 or 2 years of age, and; (v) leading to production of TNF-α or IL-1β varied by stimuli. Our data contradict the notion of a linear progression from an ‘immature’ neonatal to a ‘mature’ adult pattern, but instead indicate the existence of qualitative and quantitative age-specific changes in innate immune reactivity in response to TLR stimulation

Hox10 Genes Function in Kidney Development in the Differentiation and Integration of the Cortical Stroma

Organogenesis requires the differentiation and integration of distinct populations of cells to form a functional organ. In the kidney, reciprocal interactions between the ureter and the nephrogenic mesenchyme are required for organ formation. Additionally, the differentiation and integration of stromal cells are also necessary for the proper development of this organ. Much remains to be understood regarding the origin of cortical stromal cells and the pathways involved in their formation and function. By generating triple mutants in the Hox10 paralogous group genes, we demonstrate that Hox10 genes play a critical role in the developing kidney. Careful examination of control kidneys show that Foxd1-expressing stromal precursor cells are first observed in a cap-like pattern anterior to the metanephric mesenchyme and these cells subsequently integrate posteriorly into the kidney periphery as development proceeds. While the initial cap-like pattern of Foxd1-expressing cortical stromal cells is unaffected in Hox10 mutants, these cells fail to become properly integrated into the kidney, and do not differentiate to form the kidney capsule. Consistent with loss of cortical stromal cell function, Hox10 mutant kidneys display reduced and aberrant ureter branching, decreased nephrogenesis. These data therefore provide critical novel insights into the cellular and genetic mechanisms governing cortical cell development during kidney organogenesis. These results, combined with previous evidence demonstrating that Hox11 genes are necessary for patterning the metanephric mesenchyme, support a model whereby distinct populations in the nephrogenic cord are regulated by unique Hox codes, and that differential Hox function along the AP axis of the nephrogenic cord is critical for the differentiation and integration of these cell types during kidney organogenesis

Utility of the Health of the Nation Outcome Scales (HoNOS) in Predicting Mental Health Service Costs for Patients with Common Mental Health Problems : Historical Cohort Study

BACKGROUND: Few countries have made much progress in implementing transparent and efficient systems for the allocation of mental health care resources. In England there are ongoing efforts by the National Health Service (NHS) to develop mental health 'payment by results' (PbR). The system depends on the ability of patient 'clusters' derived from the Health of the Nation Outcome Scales (HoNOS) to predict costs. We therefore investigated the associations of individual HoNOS items and the Total HoNOS score at baseline with mental health service costs at one year follow-up.METHODS: An historical cohort study using secondary care patient records from the UK financial year 2012-2013. Included were 1,343 patients with 'common mental health problems', represented by ICD-10 disorders between F32-48. Costs were based on patient contacts with community-based and hospital-based mental health services. The costs outcome was transformed into 'high costs' vs 'regular costs' in main analyses.RESULTS: After adjustment for covariates, 11 HoNOS items were not associated with costs. The exception was 'self-injury' with an odds ratio of 1.41 (95% CI 1.10-2.99). Population attributable fractions (PAFs) for the contribution of HoNOS items to high costs ranged from 0.6% (physical illness) to 22.4% (self-injury). After adjustment, the Total HoNOS score was not associated with costs (OR 1.03, 95% CI 0.99-1.07). However, the PAF (33.3%) demonstrated that it might account for a modest proportion of the incidence of high costs.CONCLUSIONS: Our findings provide limited support for the utility of the self-injury item and Total HoNOS score in predicting costs. However, the absence of associations for the remaining HoNOS items indicates that current PbR clusters have minimal ability to predict costs, so potentially contributing to a misallocation of NHS resources across England. The findings may inform the development of mental health payment systems internationally, especially since the vast majority of countries have not progressed past the early stages of this development. Discrepancies between our findings with those from Australia and New Zealand point to the need for further international investigations

Corporate Entrepreneurship:From Structures to Mindset

Corporate entrepreneurship dispersed throughout an organization and leveraging the entrepreneurial potential of all its employees bears significant benefits for those organizations that embrace it. However, it appears more difficult to instill and requires strong investment in the development of human capital and entrepreneurial mindset among the employees and across the organization. In this chapter, we discuss the essence of corporate entrepreneurship mindset and show that across an organization, there might be different entrepreneurial mindsets that correspond to different people, opportunities, and contexts. Although different, they all lead to enactment of entrepreneurial projects. This chapter, thus, contributes to the discussion regarding the nature of corporate entrepreneurial mindsets, and their development and stimulation within an organization, from both academic and practical view