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Background: In high throughput cancer genomic studies, results from the analysis of single datasets often suffer from a lack of reproducibility because of small sample sizes. Integrative analysis can effectively pool and analyze multiple datasets and provides a cost effective way to improve reproducibility. In integrative analysis, simultaneously analyzing all genes profiled may incur high computational cost. A computationally affordable remedy is prescreening, which fits marginal models, can be conducted in a parallel manner, and has low computational cost. Results: An integrative prescreening approach is developed for the analysis of multiple cancer genomic datasets. Simulation shows that the proposed integrative prescreening has better performance than alternatives, particularly including prescreening with individual datasets, an intensity approach and meta-analysis. We also analyze multiple microarray gene profiling studies on liver and pancreatic cancers using the proposed approach. Conclusions: The proposed integrative prescreening provides an effective way to reduce the dimensionality in cancer genomic studies. It can be coupled with existing analysis methods to identify cancer markers. [ABSTRACT FROM AUTHOR]

Significance of genetic association to a marker has been traditionally evaluated through statistics that are standardized such that their null distributions conform to some known ones. Distributional assumptions are often required in this standardization procedure. Based on the observation that the phenotype remains the same regardless of the marker being investigated, we propose a simple statistic that does not need such standardization. We propose a resampling procedure to assess this statistic's genome-wide significance. This method has been applied to replicate 2 of the Genetic Analysis Workshop 17 simulated data on unrelated individuals in an attempt to map phenotype Q2. However, none of the selected SNPs are in genes that are disease-causing. This may be due to the weak effect that each genetic factor has on Q2. [ABSTRACT FROM AUTHOR]

The stamen, which consists of an anther and a filament, is the male reproductive organ in a flower. The specification of stamen identity in Arabidopsis (Arabidopsis thaliana) is controlled by a combination of the B genes APETALA3 (AP3) and PISTILLATA, the C gene AGAMOUS (AG), and the E genes SEPALLATA1 (SEP1) to SEP4. The "floral organ-building" gene SPOROCYTELESS/NOZZLE (SPL/NZZ) plays a central role in regulating anther cell differentiation. However, much less is known about how "floral organ identity" and floral organ-building genes interact to control floral organ development. In this study, we report that ectopic expression of SPL/NZZ not only affects flower development in the wild-type background but also leads to the transformation of petal-like organs into stamen-like organs in flowers of ap2-1, a weak ap2 mutant allele. Moreover, our loss-of- function analysis indicates that the spl/nzz mutant enhances the phenotype of the ag weak allele ag-4. Furthermore, ectopic expression and overexpression of SPL/NZZ altered expression of AG, SEP3, and AP2 in rosette leaves and flowers, while ectopic expression of SPL/NZZ resulted in ectopic expression of AG and SEP3 in the outer whorls of flowers. Our results indicate that the SPL/NZZ gene is engaged in controlling stamen identity via interacting with genes required for stamen identity in Arabidopsis. [ABSTRACT FROM AUTHOR]

A basic question in analyzing cDNA microarray data is normalization, the purpose of which is to remove systematic bias in the observed expression values by establishing a normalization curve across the whole dynamic range. A proper normalization procedure ensures that the normalized intensity ratios provide meaningful measures of relative expression levels. We propose a two-way semilinear model (TW-SLM) for normalization and analysis of microarray data. This method does not make the usual assumptions underlying some of the existing methods. For example, it does not assume that the percentage of differentially expressed genes is small or that there is symmetry in the expression levels of up-regulated and down-regulated genes, as required in the lowess normalization method. The TW-SLM also naturally incorporates uncertainty due to normalization into significance analysis of microarrays. We use a semiparametric approach based on polynomial splines in the TW-SLM to estimate the normalization curves and the normalized expression values. We study the theoretical properties of the proposed estimator in the TW-SLM, including the finite-sample distributional properties of the estimated gene effects and the rate of convergence of the estimated normalization curves when the number of genes under study is large. We also conduct simulation studies to evaluate the TW-SLM method and illustrate the proposed method using a published microarray dataset. [ABSTRACT FROM AUTHOR]

Presents the authors' comments on the paper "Semilinear High-Dimensional Model for Normalization of Microarray Data: A Theoretical Analysis and Partial Consistency," by Jianqing Fan, Heng Peng and Tao Huang, published in the September 2005 issue of the "Journal of the American Statistical Association." Appreciation of the authors for their significant contribution to the semiparametric estimation theory; Suggestions for a two-way semilinear model for normalization and analysis of cDNA microarray data; Comments on multiway semilinear models; Description of models for location normalization; Opinion on the relationship between the relationship between the multiway semilinear models and the semilinear in-slide model.

Motivation: Array comparative genomic hybridization (aCGH) provides a genome-wide technique to screen for copy number alteration. The existing segmentation approaches for analyzing aCGH data are based on modeling data as a series of discrete segments with unknown boundaries and unknown heights. Although the biological process of copy number alteration is discrete, in reality a variety of biological and experimental factors can cause the signal to deviate from a stepwise function. To take this into account, we propose a smooth segmentation (smoothseg) approach. Methods: To achieve a robust segmentation, we use a doubly heavy-tailed random-effect model. The first heavy-tailed structure on the errors deals with outliers in the observations, and the second deals with possible jumps in the underlying pattern associated with different segments. We develop a fast and reliable computational procedure based on the iterative weighted least-squares algorithm with band-limited matrix inversion. Results: Using simulated and real data sets, we demonstrate how smoothseg can aid in identification of regions with genomic alteration and in classification of samples. For the real data sets, smoothseg leads to smaller false discovery rate and classification error rate than the circular binary segmentation (CBS) algorithm. In a realistic simulation setting, smoothseg is better than wavelet smoothing and CBS in identification of regions with genomic alterations and better than CBS in classification of samples. For comparative analyses, we demonstrate that segmenting the t-statistics performs better than segmenting the data. Availability: The R package smoothseg to perform smooth segmentation is available from http://www.meb.ki.se/~yudpaw Contact: yudi.pawitan@ki.se [ABSTRACT FROM AUTHOR]

The interleukin-1 (IL-1) gene polymorphisms have been implicated in chronic obstructive pulmonary disease (COPD) risk, but results are controversial. We aimed to conduct a meta-analysis to address this issue. Odds ratio (OR) and 95% confidence interval (CI) were used to investigate the strength of the association. The meta-analysis revealed no association between the IL1B (-511), (-31), (+3954) polymorphisms and COPD risk. However, stratification by ethnicity indicated that the T allele carriers of the IL1B (-511) polymorphism and the C allele carriers of the IL1B (-31) variant were associated with an increased risk for developing COPD in East Asians (OR=1.61, 95% CI: 1.13-2.31, Pz=0.009 and OR=1.55, 95% CI: 1.14-2.11,Pz=0.006, respectively). The meta-analysis revealed a significant association between the IL1RN (VNTR) polymorphism and COPD risk in all study subjects and East Asians under homozygote model (22 vs. LL: OR=3.16, 95% CI: 1.23-8.13, Pz=0.017 and OR=3.20, 95% CI: 1.13-9.12, Pz=0.029, respectively). Our meta-analysis suggests that the IL1B (-511), (-31) and IL1RN (VNTR) polymorphisms are associated with COPD risk in East Asians. There is no association between the IL1B (+13954) polymorphism and COPD risk. Further studies should be performed in other ethnic groups besides East Asians. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the family genetic background of a 22-year-old man with Crigler–Najjar syndrome type II (CN-II). METHODS: After the proband (patient) with CN-II was diagnosed by liver function tests, a low calorie intake test and an oral phenobarbital enzyme-induction trial, blood samples were collected from 11 family members for identifying DNA gene groups. Exons 1–5 of the UGT1A1 gene were amplified by polymerase chain reaction (PCR) and mutations of the UGT1A1 gene were screened by a direct DNA sequencing. RESULTS: The serum unconjugated bilirubin increased in the proband from 156.4 µmol/L to 243.5 µmol/L after he started a low calorie intake, and it decreased to 51.8 µmol/L within a month of taking oral phenobarbital daily. Both functional tests and ultrasonographic images of the liver were normal except for the unconjugated hyperbilirubinemia. A missense mutation of Tyr486Asp at exon 5 in the UGT1A1 gene and a homozygous mutation were confirmed in the proband. Heterozygous mutations were found in his parents, his younger sister and three great-uncles, while no mutation of the UGT1A1 gene was detected in the remaining four family members. CONCLUSION: A missense mutation of Tyr486Asp is considered to be the cause of the CN-II in this patient. It is a recessive trait that is autosomally inherited in this family. No influence of the mutation was found on the response elements for phenobarbital in the promoter region. [ABSTRACT FROM AUTHOR]

We describe a method for mapping quantitative trait loci that allows for locus heterogeneity. A genome-wide linkage analysis of blood pressure was performed using sib-pair data from the Framingham Heart Study. Evidence of linkage was found on four markers (GATA89G08, GATA23D06, GATA14E09, and 049xd2) at a significance level of 0.01. Two of them (GATA14E09 and 049xd2) seem to overlap with linkage signals reported previously, while the other two are not linked to any known signals. [ABSTRACT FROM AUTHOR]

Background/Aims: The colorectal neoplasia differentially expressed (CRNDE) gene is a long noncoding RNA (lncRNAs) that is upregulated in colorectal cancer and glioma. Here, we investigated the regulatory function of CRNDE in gastric cancer (GC). Methods: CRNDE and miR-145 expression were assayed by qRT-PCR, and E2F3 protein expression was measured by western blotting. A luciferase reporter assay was used to detect the direct regulation of miR-145 by CRNDE. Cell viability and colony formation of human GC cells were detected using MTT and colony formation assay, respectively. Results: CRNDE was highly expressed in GC cell lines and tissues; overexpression of CRNDE increased GC cell viability and promoted colony formation. Knockdown of CRNDE did not result in loss of expression-related effects on cell proliferation and colony formation. Further investigation revealed that the miR-145 target gene E2F3 was strongly expressed following CRNDE competitive molecular sponging of miR- 145. Conclusion: CRNDE acted as a growth-promoting lncRNA in GC and maybe a potential target of GC treatment. [ABSTRACT FROM AUTHOR]

Background and Aim: The aim of this study was to investigate the influence of polygenetic polymorphisms, which play a role in the pathogenesis of metabolic syndrome, on the susceptibility to non-alcoholic fatty liver disease (NAFLD) of Chinese people. Methods: The subjects were selected from an epidemiological survey in the Guangdong province of southern China. In each polymorphism study, 50–117 subjects who met the diagnostic criteria of NAFLD and had typical clinical and ultrasonographic findings were placed into the case group. Using a nested case–control design, the same numbers of matched people without NAFLD were included as controls. Single nucleotide polymorphisms (SNP) at nine positions in seven candidate genes were tested. These SNP were found to be associated with the pathogenesis of metabolic syndrome. Genetic analyses were performed using genomic DNA extracted from peripheral blood leukocytes. Polymerase chain reaction–restriction fragment length polymorphism was applied to detect SNP. Results: Most candidate genes' SNP were associated with susceptibility to NAFLD. Some showed positive relationships (increased risk): tumor necrosis factor-α-238, adiponectin-45, leptin-2548, peroxisome proliferator-activated receptors-161 and phosphatidyletha-nolamine N-methyltransferase-175. Other SNP demonstrated a negative association (decreased risk): adiponectin-276 and hepatic lipase-514. Only two were not associated: tumor necrosis factor-α-380 and peroxisome proliferator-activated receptors-γ co-activator-1α-482. Conclusion: Most candidate genes' SNP examined in metabolic syndrome patients were associated with susceptibility to NAFLD. [ABSTRACT FROM AUTHOR]

Background and Aims: Studies have shown that the vitamin D receptor (VDR) gene polymorphisms may be associated with pulmonary tuberculosis (TB) and play important roles in the regulation of calcium in a variety of tissues including bone. To our knowledge, however, whether FokI polymorphism in VDR gene is associated with susceptibility to spinal TB is still unknown. We undertook this study to investigate the association between FokI polymorphism in VDR gene and susceptibility to spinal TB in Chinese Han population. Methods: This study included 110 patients with spinal TB and 102 volunteers as controls. FokI polymorphism in VDR gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in the spinal TB group and the control group. The frequencies of VDR-FokI genotypes in the two groups were compared using χ2 test. Results: There was a significant difference between groups in regard to the frequencies of the VDR-FokI genotypes (p <0.05). In the spinal TB group, the frequency of the ff genotype was 46.36%, which was significantly higher than the corresponding value for the control group (28.43%). Furthermore, the odds ratio (OR) was 2.176 (p <0.05), and the 95% confidence interval (CI) ranged from 1.236–3.832. Conclusions: FokI polymorphism in VDR gene may be associated with the susceptibility to spinal TB in Chinese Han population. Furthermore, the ff genotype may be the susceptible genotype of spinal TB. [Copyright &y& Elsevier]