With an overall prevalence of 10-20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries. We performed an ...association scan of >500,000 SNPs in 280 individuals with gallstones and 360 controls. A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in ABCG8 (allelic P value P(CCA) = 4.1 x 10(-9)), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German (P = 2.8 x 10(-7)) and 167 Chilean subjects (P = 0.02). The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8-2.6, P = 1.4 x 10(-14)) in the full German sample. Association was stronger in subjects with cholesterol gallstones (odds ratio = 3.3), suggesting that His19 might be associated with a more efficient transport of cholesterol into the bile.
Cross-efficiency evaluation, an extension of data envelopment analysis (DEA), can eliminate unrealistic weighing schemes and provide a ranking for decision making units (DMUs). In the literature, the ...determination of input and output weights uniquely receives more attentions. However, the problem of choosing the aggressive (minimal) or benevolent (maximal) formulation for decision-making might still remain. In this paper, we develop a procedure to perform cross-efficiency evaluation without the need to make any specific choice of DEA weights. The proposed procedure takes into account the aggressive and benevolent formulations at the same time, and the choice of DEA weights can then be avoided. Consequently, a number of cross-efficiency intervals is obtained for each DMU. The entropy, which is based on information theory, is an effective tool to measure the uncertainty. We then utilize the entropy to construct a numerical index for DMUs with cross-efficiency intervals. A mathematical program is proposed to find the optimal entropy values of DMUs for comparison. With the derived entropy value, we can rank DMUs accordingly. Two examples are illustrated to show the effectiveness of the idea proposed in this paper.
The selection of advanced manufacturing technologies (AMTs) is an essential yet complex decision that requires careful consideration of various performance criteria. In real-world applications, there ...are cases that observations are difficult to measure precisely, observations are represented as linguistic terms, or the data need to be estimated. Since the growth of engineering sciences has been the key reason for the increased utilization of AMTs, this paper develops a fuzzy network data envelopment analysis (DEA) to the selection of AMT alternatives considering multiple decision-makers (DMs) and weight restrictions when the input and output data are represented as fuzzy numbers. By viewing the multiple DMs as a network one, the data provided by each DM can then be taken into account in evaluating the overall performances of AMT alternatives. In the solution process, we obtain the overall and DMs efficiency scores of each AMT alternative at the same time, and a relationship in which the former is a weighted average of the latter is also derived. Since the final evaluation results of AMTs are fuzzy numbers, a ranking procedure is employed to determine the most preferred one. An example is used to illustrate the applicability of the proposed methodology.
Cross-efficiency evaluation effectively distinguishes a set of decision-making units (DMUs) via self- and peer-evaluations. In constant returns to scale, this evaluation technique is usually applied ...for data envelopment analysis (DEA) models because negative efficiencies will not occur in this case. For situations of variable returns to scale, the negative cross-efficiencies may occur in this evaluation method. In the real world, the observations could be uncertain and difficult to measure precisely. The existing fuzzy cross-evaluation methods are restricted to production technologies with constant returns to scale. Generally, symmetry is a fundamental characteristic of binary relations used when modeling optimization problems. Additionally, the notion of symmetry appeared in many studies about uncertain theories employed in DEA problems, and this approach can be considered an engineering tool for supporting decision-making. This paper proposes a fuzzy cross-efficiency evaluation model with fuzzy observations under variable returns to scale. Since all possible weights of all DMUs are considered, a choice of weights is not required. Most importantly, negative cross-efficiencies are not produced. An example shows that this paper’s fuzzy cross-efficiency evaluation method has discriminative power in ranking the DMUs when observations are fuzzy numbers.
Objective. Lipid abnormalities contribute to the increased risk of premature atherosclerosis in patients with SLE. This study was undertaken to investigate changes in lipid profile after B-cell ...depletion therapy (BCDT) in patients with active SLE who had failed standard immunosuppressive therapy. Methods. Twelve patients with refractory SLE treated with BCDT based on rituximab (two biweekly infusions of 1 g) were examined. Lipid profile and lupus activity were measured before the infusions and 1 year later. The control group consisted of 26 age- and sex-matched lupus patients not treated with BCDT. Results. In the study group, the mean levels of total, high-density lipoprotein (HDL) and low-density lipoprotein cholesterols were 4.6, 1.4 and 2.4 mmol/l at baseline and changed to 4.1, 1.6 and 2.0 mmol/l (P = NS, P = 0.04 and P = NS) at 1 year, respectively. The atherogenic index was 3.8 at baseline and decreased to 2.7 (P = 0.02). The triglyceride (TG) level was 2.1 mmol/l at baseline and decreased to 1.3 mmol/l (P = 0.04). BCDT was followed by a significant decrease in global BILAG scores and a drop in the mean dose of prednisolone at 1 year (P = 0.01). Reduction in disease activity was significantly associated with a reduction in total cholesterol and TG levels and an increase in HDL cholesterol levels. In the control group, there were no differences in any of the lipid determinations over a 1-year period. Conclusion. This provisional observational study suggests a favourable long-term effect of BCDT on the lipid profile of patients with refractory SLE, which correlated with decreasing activity of the disease.
The primary objective of most gene expression studies is the identification of one or more gene signatures; lists of genes whose transcriptional levels are uniquely associated with a specific ...biological phenotype. Whilst thousands of experimentally derived gene signatures are published, their potential value to the community is limited by their computational inaccessibility. Gene signatures are embedded in published article figures, tables or in supplementary materials, and are frequently presented using non-standard gene or probeset nomenclature. We present GeneSigDB (http://compbio.dfci.harvard.edu/genesigdb) a manually curated database of gene expression signatures. GeneSigDB release 1.0 focuses on cancer and stem cells gene signatures and was constructed from more than 850 publications from which we manually transcribed 575 gene signatures. Most gene signatures (n = 560) were successfully mapped to the genome to extract standardized lists of EnsEMBL gene identifiers. GeneSigDB provides the original gene signature, the standardized gene list and a fully traceable gene mapping history for each gene from the original transcribed data table through to the standardized list of genes. The GeneSigDB web portal is easy to search, allows users to compare their own gene list to those in the database, and download gene signatures in most common gene identifier formats.
Previous studies of human Y-chromosomal single-nucleotide polymorphisms (Y-SNPs) established a link between the extant Y-SNP haplogroup distribution and the prehistoric demography of Europe. By ...contrast, our analysis of seven rapidly evolving Y-chromosomal short tandem repeat loci (Y-STRs) in over 12,700 samples from 91 different locations in Europe reveals a signature of more recent historic events, not previously detected by other genetic markers. Cluster analysis based upon molecular variance yields two clearly identifiable sub-clusters of Western and Eastern European Y-STR haplotypes, and a diverse transition zone in central Europe, where haplotype spectra change more rapidly with longitude than with latitude. This and other observed patterns of Y-STR similarity may plausibly be related to particular historical incidents, including, for example, the expansion of the Franconian and Ottoman Empires. We conclude that Y-STRs may be capable of resolving male genealogies to an unparalleled degree and could therefore provide a useful means to study local population structure and recent demographic history.
Objective. To compare the clinical results after treatment with B-cell depleting therapy in patients with membranous (WHO Class V) vs proliferative (WHO Class III or IV) lupus nephritis (LN). ...Methods. Data were compiled from two European centres on all patients with LN who were treated with i.v. rituximab (RTX) in a combination protocol with i.v. cyclophosphamide and steroids. Laboratory and serological evaluations were performed at 3, 6 and 12 months of follow-up. No immunosuppressive drugs were given before B-cell repopulation. Results. Forty-three patients, 28 with proliferate and 15 with membranous LN by renal biopsy, were evaluated. Six months after treatment with RTX, both the membranous and the proliferative LN patients had a significant reduction in proteinuria and an increase in serum albumin. The main improvements were observed during the first 6 months and only minor non-significant changes in albumin and proteinuria were observed thereafter. As expected, the patients with membranous nephritis had lower anti-dsDNA titres and higher complement C3 levels at baseline, but in both groups a significant reduction in anti-dsDNA titre and improvements in complement C3 levels were seen during the first 6 months after treatment; the kinetics of improvement were similar in both groups. Conclusion. The clinical course following B-cell depleting therapy is strikingly similar between patients with membranous and those with proliferative LN. These observational data suggest that, if controlled studies confirm the efficacy of B-cell depleting therapy in proliferative nephritis, clinicians may reasonably consider such therapy in membranous LN.
The differential pathophysiologic mechanisms that trigger and maintain the two forms of inflammatory bowel disease (IBD), Crohn disease (CD), and ulcerative colitis (UC) are only partially ...understood. cDNA microarrays can be used to decipher gene regulation events at a genome-wide level and to identify novel unknown genes that might be involved in perpetuating inflammatory disease progression.
High-density cDNA microarrays representing 33,792 UniGene clusters were prepared. Biopsies were taken from the sigmoid colon of normal controls (n = 11), CD patients (n = 10) and UC patients (n = 10). 33P-radiolabeled cDNA from purified poly(A)+ RNA extracted from biopsies (unpooled) was hybridized to the arrays. We identified 500 and 272 transcripts differentially regulated in CD and UC, respectively. Interesting hits were independently verified by real-time PCR in a second sample of 100 individuals, and immunohistochemistry was used for exemplary localization. The main findings point to novel molecules important in abnormal immune regulation and the highly disturbed cell biology of colonic epithelial cells in IBD pathogenesis, e.g., CYLD (cylindromatosis, turban tumor syndrome) and CDH11 (cadherin 11, type 2). By the nature of the array setup, many of the genes identified were to our knowledge previously uncharacterized, and prediction of the putative function of a subsection of these genes indicate that some could be involved in early events in disease pathophysiology.
A comprehensive set of candidate genes not previously associated with IBD was revealed, which underlines the polygenic and complex nature of the disease. It points out substantial differences in pathophysiology between CD and UC. The multiple unknown genes identified may stimulate new research in the fields of barrier mechanisms and cell signalling in the context of IBD, and ultimately new therapeutic approaches.
Previous studies have demonstrated an increased risk of breast cancer among patients with systemic sclerosis (scleroderma). To describe the clinical characteristics of 21 patients with both systemic ...sclerosis and breast cancer, and compare their risk factors to female scleroderma patients without breast cancer, in a population-based cohort study of South Australia. Subjects with scleroderma and breast cancer were identified from the South Australian Scleroderma Register with cross-linking to the South Australian Cancer Registry, last updated to the end of December 2005. Clinical information was obtained from standardised self-administered questionnaires and case note reviews. Odds ratios for the risk factors for breast cancer in scleroderma were determined, and clinical variables were analysed using chi square, Fisher’s exact, Mann–Whitney and
t
tests. At the end of December 2005 there were a total of 389 female patients with scleroderma. Of these, 21 (5.4%) had been diagnosed with breast cancer. The mean age of onset of scleroderma was 43.5 years, and the mean age of breast cancer was 60.5 years in those with scleroderma and breast cancer. The majority (71.4%) had limited scleroderma, with anti-centromere antibody being the most prevalent serological abnormality. In 16 (76%) patients the diagnosis of breast cancer occurred on an average of 22.3 years after the onset of their first scleroderma symptom. When compared to 48 controls, scleroderma patients with breast cancer were found to have a higher incidence of a positive family history of breast cancer (Fisher’s exact test,
p
= 0.04) and a lower incidence of hormone-replacement therapy use (Fisher’s exact test,
p
= 0.0026). This population-based cohort study provides evidence that the majority of patients with scleroderma and breast cancer have limited scleroderma and anti-centromere antibody. Given the increased incidence of solid tumours in systemic sclerosis, we suggest regular screening of female patients for breast cancer, especially in those with a family history.
PDF
