Haplotype-based quantitative trait mapping using a clustering algorithm

BACKGROUND: With the availability of large-scale, high-density single-nucleotide polymorphism (SNP) markers, substantial effort has been made in identifying disease-causing genes using linkage disequilibrium (LD) mapping by haplotype analysis of unrelated individuals. In addition to complex diseases, many continuously distributed quantitative traits are of primary clinical and health significance. However the development of association mapping methods using unrelated individuals for quantitative traits has received relatively less attention. RESULTS: We recently developed an association mapping method for complex diseases by mining the sharing of haplotype segments (i.e., phased genotype pairs) in affected individuals that are rarely present in normal individuals. In this paper, we extend our previous work to address the problem of quantitative trait mapping from unrelated individuals. The method is non-parametric in nature, and statistical significance can be obtained by a permutation test. It can also be incorporated into the one-way ANCOVA (analysis of covariance) framework so that other factors and covariates can be easily incorporated. The effectiveness of the approach is demonstrated by extensive experimental studies using both simulated and real data sets. The results show that our haplotype-based approach is more robust than two statistical methods based on single markers: a single SNP association test (SSA) and the Mann-Whitney U-test (MWU). The algorithm has been incorporated into our existing software package called HapMiner, which is available from our website at . CONCLUSION: For QTL (quantitative trait loci) fine mapping, to identify QTNs (quantitative trait nucleotides) with realistic effects (the contribution of each QTN less than 10% of total variance of the trait), large samples sizes (≥ 500) are needed for all the methods. The overall performance of HapMiner is better than that of the other two methods. Its effectiveness further depends on other factors such as recombination rates and the density of typed SNPs. Haplotype-based methods might provide higher power than methods based on a single SNP when using tag SNPs selected from a small number of samples or some other sources (such as HapMap data). Rank-based statistics usually have much lower power, as shown in our study

Logistics service provider selection for disaster preparation: a socio-technical systems perspective

Since 1990s, the world has seen a lot of advances in providing humanitarian aid through sophisticated logistics operations. The current consensus seems to be that humanitarian relief organizations (HROs) can improve their relief operations by collaborating with logistics service providers (CLSPs) in the commercial sector. The question remains: how can HROs select the most appropriate CLSP for disaster preparation? Despite its practical significance, no explicit effort has been done to identify the criteria/factors in prioritising and selecting a CLSP for disaster relief. The present study aims to address this gap by consolidating the list of criteria from a socio-technical systems (STS) perspective. Then, to handle the interdependence among the criteria derived from the STS, we develop a hybrid multi-criteria decision making model for CLSP selection in the disaster preparedness stage. The proposed model is then evaluated by a real-life case study, providing insights into the decision-makers in both HROs and CLSPs

Psychiatric inpatient expenditures and public health insurance programmes: analysis of a national database covering the entire South Korean population

<p>Abstract</p> <p>Background</p> <p>Medical spending on psychiatric hospitalization has been reported to impose a tremendous socio-economic burden on many developed countries with public health insurance programmes. However, there has been no in-depth study of the factors affecting psychiatric inpatient medical expenditures and differentiated these factors across different types of public health insurance programmes. In view of this, this study attempted to explore factors affecting medical expenditures for psychiatric inpatients between two public health insurance programmes covering the entire South Korean population: National Health Insurance (NHI) and National Medical Care Aid (AID).</p> <p>Methods</p> <p>This retrospective, cross-sectional study used a nationwide, population-based reimbursement claims dataset consisting of 1,131,346 claims of all 160,465 citizens institutionalized due to psychiatric diagnosis between January 2005 and June 2006 in South Korea. To adjust for possible correlation of patients characteristics within the same medical institution and a non-linearity structure, a Box-Cox transformed, multilevel regression analysis was performed.</p> <p>Results</p> <p>Compared with inpatients 19 years old or younger, the medical expenditures of inpatients between 50 and 64 years old were 10% higher among NHI beneficiaries but 40% higher among AID beneficiaries. Males showed higher medical expenditures than did females. Expenditures on inpatients with schizophrenia as compared to expenditures on those with neurotic disorders were 120% higher among NHI beneficiaries but 83% higher among AID beneficiaries. Expenditures on inpatients of psychiatric hospitals were greater on average than expenditures on inpatients of general hospitals. Among AID beneficiaries, institutions owned by private groups treated inpatients with 32% higher costs than did government institutions. Among NHI beneficiaries, inpatients medical expenditures were positively associated with the proportion of patients diagnosed into dementia or schizophrenia categories. However, for AID beneficiaries, inpatient medical expenditures were positively associated with the proportion of all patients with a psychiatric diagnosis that were AID beneficiaries in a medical institution.</p> <p>Conclusions</p> <p>This study provides evidence that patient and institutional factors are associated with psychiatric inpatient medical expenditures, and that they may have different effects for beneficiaries of different public health insurance programmes. Policy efforts to reduce psychiatric inpatient medical expenditures should be made differently across the different types of public health insurance programmes.</p

The Hepatitis E Virus Polyproline Region Is Involved in Viral Adaptation

Genomes of hepatitis E virus (HEV), rubivirus and cutthroat virus (CTV) contain a region of high proline density and low amino acid (aa) complexity, named the polyproline region (PPR). In HEV genotypes 1, 3 and 4, it is the only region within the non-structural open reading frame (ORF1) with positive selection (4–10 codons with dN/dS>1). This region has the highest density of sites with homoplasy values >0.5. Genotypes 3 and 4 show ∼3-fold increase in homoplastic density (HD) in the PPR compared to any other region in ORF1, genotype 1 does not exhibit significant HD (p<0.0001). PPR sequence divergence was found to be 2-fold greater for HEV genotypes 3 and 4 than for genotype 1. The data suggest the PPR plays an important role in host-range adaptation. Although the PPR appears to be hypervariable and homoplastic, it retains as much phylogenetic signal as any other similar sized region in the ORF1, indicating that convergent evolution operates within the major HEV phylogenetic lineages. Analyses of sequence-based secondary structure and the tertiary structure identify PPR as an intrinsically disordered region (IDR), implicating its role in regulation of replication. The identified propensity for the disorder-to-order state transitions indicates the PPR is involved in protein-protein interactions. Furthermore, the PPR of all four HEV genotypes contains seven putative linear binding motifs for ligands involved in the regulation of a wide number of cellular signaling processes. Structure-based analysis of possible molecular functions of these motifs showed the PPR is prone to bind a wide variety of ligands. Collectively, these data suggest a role for the PPR in HEV adaptation. Particularly as an IDR, the PPR likely contributes to fine tuning of viral replication through protein-protein interactions and should be considered as a target for development of novel anti-viral drugs

Nutraceutical agents with anti-inflammatory properties prevent dietary saturated-fat induced disturbances in blood-brain barrier function in wild-type mice

Background: Emerging evidence suggests that disturbances in the blood–brain barrier (BBB) may be pivotal to the pathogenesis and pathology of vascular-based neurodegenerative disorders. Studies suggest that heightened systemic and central inflammations are associated with BBB dysfunction. This study investigated the effect of the anti-inflammatory nutraceuticals garlic extract-aged (GEA), alpha lipoic acid (ALA), niacin, and nicotinamide (NA) in a murine dietary-induced model of BBB dysfunction. Methods: C57BL/6 mice were fed a diet enriched in saturated fatty acids (SFA, 40% fat of total energy) for nine months to induce systemic inflammation and BBB disturbances. Nutraceutical treatment groups included the provision of either GEA, ALA, niacin or NA in the positive control SFA-group and in low-fat fed controls. Brain parenchymal extravasation of plasma derived immunoglobulin G (IgG) and large macromolecules (apolipoprotein (apo) B lipoproteins) measured by quantitative immunofluorescent microscopy, were used as markers of disturbed BBB integrity. Parenchymal glial fibrillar acidic protein (GFAP) and cyclooxygenase-2 (COX-2) were considered in the context of surrogate markers of neurovascular inflammation and oxidative stress. Total anti-oxidant status and glutathione reductase activity were determined in plasma.Results: Brain parenchymal abundance of IgG and apoB lipoproteins was markedly exaggerated in mice maintained on the SFA diet concomitant with significantly increased GFAP and COX-2, and reduced systemic antioxidative status. The nutraceutical GEA, ALA, niacin, and NA completely prevented the SFA-induced disturbances of BBB and normalized the measures of neurovascular inflammation and oxidative stress. Conclusions: The anti-inflammatory nutraceutical agents GEA, ALA, niacin, or NA are potent inhibitors of dietary fat-induced disturbances of BBB induced by systemic inflammations

C. elegans EIF-3.K Promotes Programmed Cell Death through CED-3 Caspase

Programmed cell death (apoptosis) is essential for the development and homeostasis of metazoans. The central step in the execution of programmed cell death is the activation of caspases. In C. elegans, the core cell death regulators EGL-1(a BH3 domain-containing protein), CED-9 (Bcl-2), and CED-4 (Apaf-1) act in an inhibitory cascade to activate the CED-3 caspase. Here we have identified an additional component eif-3.K (eukaryotic translation initiation factor 3 subunit k) that acts upstream of ced-3 to promote programmed cell death. The loss of eif-3.K reduced cell deaths in both somatic and germ cells, whereas the overexpression of eif-3.K resulted in a slight but significant increase in cell death. Using a cell-specific promoter, we show that eif-3.K promotes cell death in a cell-autonomous manner. In addition, the loss of eif-3.K significantly suppressed cell death-induced through the overexpression of ced-4, but not ced-3, indicating a distinct requirement for eif-3.K in apoptosis. Reciprocally, a loss of ced-3 suppressed cell death induced by the overexpression of eif-3.K. These results indicate that eif-3.K requires ced-3 to promote programmed cell death and that eif-3.K acts upstream of ced-3 to promote this process. The EIF-3.K protein is ubiquitously expressed in embryos and larvae and localizes to the cytoplasm. A structure-function analysis revealed that the 61 amino acid long WH domain of EIF-3.K, potentially involved in protein-DNA/RNA interactions, is both necessary and sufficient for the cell death-promoting activity of EIF-3.K. Because human eIF3k was able to partially substitute for C. elegans eif-3.K in the promotion of cell death, this WH domain-dependent EIF-3.K-mediated cell death process has potentially been conserved throughout evolution

Association of sustained virologic response with reduced progression to liver cirrhosis in elderly patients with chronic hepatitis C

Chih-Wei Tseng,1,2 Ting-Tsung Chang,3,4 Shinn-Jia Tzeng,5 Yu-Hsi Hsieh,1,2 Tsung-Hsing Hung,1,2 Hsiang-Ting Huang,6 Shu-Fen Wu,7 Kuo-Chih Tseng1,2 1Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, 2School of Medicine, Tzuchi University, Hualien, 3Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, 4Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, 5Department of Agronomy, National Chiayi University, 6Department of Nursing, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 7Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan Objective: We studied the effect of sustained virologic response (SVR) after treatment with pegylated-interferon (PEG-IFN) plus ribavirin on the development of liver cirrhosis in elderly patients with chronic hepatitis C (CHC). Patients and methods: This retrospective study enrolled 145 elderly CHC patients (aged&nbsp;&ge;65&nbsp;years) who were treatment-na&iuml;ve and were treated with PEG-IFN plus ribavirin for 6&nbsp;months between January 2005 and December 2011. Abdominal sonography was performed and liver biochemistry was studied at baseline, at the end of treatment, and every 3&ndash;6 months thereafter. The development of liver cirrhosis and related complications was evaluated at the follow-ups. The aspartate aminotransferase-to-platelet ratio index was used as a noninvasive maker for fibrosis. Results: The mean patient age was 69.1&plusmn;3.3&nbsp;years, and the average follow-up time was 5.5&nbsp;years (standard deviation: 2.5&nbsp;years, range: 1.1&ndash;12.3&nbsp;years). Ninety-five patients (65.5%) achieved SVR, and 26 (17.9%) discontinued treatment. Twenty-seven patients (18.6%) developed liver cirrhosis after treatment. Patients without SVR had significantly greater risk of liver cirrhosis than those with SVR (hazard ratio [HR]: 3.39, 95% confidence interval [CI]: 1.312&ndash;8.761, P=0.012). The difference in 3-year cumulative incidence of liver cirrhosis was 24.8% greater for patients without SVR (35.2%, 95% CI: 13.0&ndash;57.5, P=0.012) compared with those with SVR (10.4%, 95% CI: 3.1&ndash;17.7). There was a trend of a higher baseline aspartate aminotransferase-to-platelet ratio index score in patients who progressed to liver cirrhosis compared with those who did not progress (2.1&plusmn;1.2 vs 1.6&plusmn;1.3, P=0.055), but the difference failed to reach significance by Cox regression (adjusted HR: 1.285, 95% CI: 0.921&ndash;1.791, P=0.14). Conclusion: An SVR following PEG-IFN combination treatment can reduce the risk of liver cirrhosis in elderly CHC patients. Keywords: hepatitis C, sustained virologic response, pegylated interferon, ribavirin, liver cirrhosi