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Qing Lan,
Chao A Hsiung,
Keitaro Matsuo,
Yun-Chul Hong,
Adeline Seow,
Zhaoming Wang,
H Dean Hosgood,
Kexin Chen,
Jiu-Cun Wang,
Nilanjan Chatterjee, [......],
Hsien-Chih Lin,
Tangchun Wu,
Yi-Long Wu,
Pan-Chyr Yang,
Baosen Zhou,
Min-Ho Shin,
Joseph F Fraumeni,
Dongxin Lin,
Stephen J Chanock,
Nathaniel Rothman
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ABSTRACT: To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10(-6)) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10(-18)), 6q22.2 (rs9387478, P = 4.14 × 10(-10)) and 6p21.32 (rs2395185, P = 9.51 × 10(-9)). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
Nature Genetics 11/2012; · 35.53 Impact Factor
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ABSTRACT: RNA interference (RNAi) is an endogenous cellular process in which small double-stranded RNAs lead to the destruction of mRNAs with complementary nucleoside sequence. With the production of RNAi libraries, large-scale RNAi screening in human cells can be conducted to identify unknown genes involved in a biological pathway. One challenge researchers face is how to deal with the multiple testing issue and the related false positive rate (FDR) and false negative rate (FNR). This paper proposes a Bayesian hierarchical measurement error model for the analysis of data from a two-channel RNAi high-throughput experiment with replicates, in which both the activity of a particular biological pathway and cell viability are monitored and the goal is to identify short hair-pin RNAs (shRNAs) that affect the pathway activity without affecting cell activity. Simulation studies demonstrate the flexibility and robustness of the Bayesian method and the benefits of having replicates in the experiment. This method is illustrated through analyzing the data from a RNAi high-throughput screening that searches for cellular factors affecting HCV replication without affecting cell viability; comparisons of the results from this HCV Study and some of those reported in the literature are included.
The Annals of Applied Statistics 03/2012; 6(1):356-382. · 1.58 Impact Factor
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H Dean Hosgood, Wen-Chang Wang,
Yun-Chul Hong,
Jiu-Cun Wang,
Kexin Chen,
I-Shou Chang,
Chien-Jen Chen,
Daru Lu,
Zhihua Yin,
Chen Wu, [......],
Fang-Yu Tsai,
Pan-Chyr Yang,
Joseph F Fraumeni,
Adeline Seow,
Dongxin Lin,
Baosen Zhou,
Stephen Chanock,
Chao Agnes Hsiung,
Nathaniel Rothman,
Qing Lan
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ABSTRACT: A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10(-12)); however, this association did not achieve genome-wide significance (p ≤ 10(-7)) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10(-8); allelic risk = 0.80, 95% confidence interval (CI) = 0.74-0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67-0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.
Human Genetics 02/2012; 131(7):1197-203. · 5.07 Impact Factor
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02/2012; , ISBN: 978-953-51-0028-7
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ABSTRACT: We present a model-free approach to the study of the number of false discoveries for large-scale simultaneous family-based association tests (FBATs) in which the set of discoveries is decided by applying a threshold to the test statistics. When the association between a set of markers in a candidate gene and a group of phenotypes is studied by a class of FBATs, we indicate that a joint null hypothesis distribution for these statistics can be obtained by the fundamental statistical method of conditioning on sufficient statistics for the null hypothesis. Based on the joint null distribution of these statistics, we can obtain the distribution of the number of false discoveries for the set of discoveries defined by a threshold; the size of this set is referred to as its tail count. Simulation studies are presented to demonstrate that the conditional, not the unconditional, distribution of the tail count is appropriate for the study of false discoveries. The usefulness of this approach is illustrated by re-examining the association between PTPN1 and a group of blood-pressure-related phenotypes reported by Olivier et al. (Hum Mol Genet 13:1885-1892, 2004); our results refine and reinforce this association.
Human Genetics 12/2010; 129(4):425-32. · 5.07 Impact Factor
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Chao Agnes Hsiung,
Qing Lan,
Yun-Chul Hong,
Chien-Jen Chen,
H Dean Hosgood,
I-Shou Chang,
Nilanjan Chatterjee,
Paul Brennan,
Chen Wu,
Wei Zheng, [......],
Chih-Yi Chen,
Kun-Chieh Chen,
Shi-Yi Yang,
Chi-Yuan Hu,
Chung-Kai Chang,
Joseph F Fraumeni,
Stephen Chanock,
Pan-Chyr Yang,
Nathaniel Rothman,
Dongxin Lin
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ABSTRACT: Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10(-7) or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30 x 10(-11)). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38 x 10(-11)). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60 x 10(-20), allelic risk = 1.54, 95% Confidence Interval (CI) 1.41-1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40-1.87), and 2.35 (95% CI: 1.95-2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.
PLoS Genetics 08/2010; 6(8). · 8.69 Impact Factor
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ABSTRACT: Cardiac dysfunction after severe burn is associated with postburn myocardial injury. We hypothesize that myocyte apoptosis is triggered and presented as the pathologic basis of postburn myocardial injury during the early stage after severe burn, and that apoptosis may be related to inflammatory responses in the postburn myocardium.
Rats with 40% total body surface area full-thickness burn were used. The following functions were measured at several time points after the burn injury: myocyte apoptosis (TUNEL staining, DNA ladder, and caspase-3 activity assay); mRNA levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (reverse transcriptase-polymerase chain reaction [RT-PCR]); activities of myeloperoxidase and p38 mitogen activated protein (MAP) kinase (Western blots); and left cardiac function.
TUNEL positive myocytes appeared as early as 6-hour and their numbers showed further increases at 12-hour and 24-hour postburn; DNA fragmentation was clearly observed, and caspase-3 activity was significantly increased in the myocardium after burn. Infiltration of neutrophils, evidenced by the levels of myeloperoxidase activity, expression of TNF-alpha, and p38 MAP kinase activity in the heart, were all significantly increased within 24-hour after burn. Cardiac function was decreased after burn, which approximately paralleled the increased amount of cardiac apoptosis.
These results demonstrate that cardiomyocyte apoptosis progressively develops during the early stage after severe burn, which may in part contribute to burn-induced cardiac dysfunction. Myocardial inflammatory responses, evidenced by the increased infiltration of neutrophils, as well as production of TNF-alpha probably because of the activation of p38 MAP kinase, may be involved in burn-induced cardiomyocyte apoptosis.
The Journal of trauma 09/2008; 65(2):401-8; discussion 408. · 2.48 Impact Factor
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ABSTRACT: The demand for a content-based 3D model retrieval system becomes urgent. Hence, we propose a novel feature, called principal plane descriptor (PPD), for 3D model retrieval. The experiments are conducted on a 3D model database. Experiment results show that our proposed method is superior to others.
Innovative Computing, Information and Control, 2007. ICICIC '07. Second International Conference on; 10/2007
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ABSTRACT: For a genetic study in which there are concordant and discordant sibpairs for a complex disease trait and the measurements of other endophenotypes/intermediate phenotypes for each of the individuals are also available, we describe an allele-sharing based multipoint linkage test that utilizes nonparametrically the additional endophenotypes/intermediate phenotypes. The usefulness of this method is evaluated in simulation studies, which show that the gain in power is influenced by not only the endophenotypic value but also the correlation between the diagnosis-based phenotype and the endophenotype. In addition to reporting p values, our method also provides an index C(E), derived from the coefficients of the weight function associated with the endophenotype in the proposed statistic, to indicate the relevance of a specific endophenotype/intermediate phenotype in the genetic study. The simulation study indicates that a larger power, in general, corresponds to a larger value of the index C(E). The index C(E) is thus suggested as a quantity to be used in the choice of endophenotypes in linkage study. Data from the Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe) are used to illustrate the method.
Genetic Epidemiology 03/2006; 30(2):133-42. · 3.44 Impact Factor
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Zi-Yuan Zhou,
Toshiro Takezaki,
Bao-Qing Mo,
Hua-Ming Sun, Wen-Chang Wang,
Li-Ping Sun,
Sheng-Xue Liu,
Lin Ao,
Guo-Hua Cheng,
Ying-Ming Wang,
Jia Cao,
Kazuo Tajima
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ABSTRACT: Nationwide surveys of food and nutrient intake in China have revealed geographical variation between urban and rural areas. This study developed a semi-quantitative food frequency questionnaire (SQFFQ) for cancer risk assessment suitable for both urban and rural populations by conducting a survey of food intake in Chongqing, China. We recruited 100 urban and 104 rural healthy residents aged from 35 to 55 years in Chongqing, and collected dietary data with 3-day weighed records to assist in the development of the SQFFQ. The intake of 35 nutrients was calculated according to Standard Food Composition Tables for China and Japan. For each nutrient estimated by percentage contribution analysis (CA) and multiple regression analysis (MRA), foods with up to a 90% contribution or a 0.90 cumulative R(2) were selected as items for SQFFQs. The food items of the combined SQFFQ were selected from all items listed in either urban or rural SQFFQs. Mean intake of energy, protein and carbohydrate did not differ between the urban and rural residents. The latter consumed more fat than their urban counterparts. We selected 119 food items for the combined SQFFQ, comprising 22 specific items for the urban SQFFQ, 6 for the rural, and 78 common and 13 additional items. The combined SQFFQ covered 33 nutrients with up to a 90% contribution in each area. We were able to develop a data-based SQFFQ that can estimate nutrient intake of both urban and rural populations, with suitable coverage rates. Further reliability and reproducibility tests are now needed to assess its applicability.
Asia Pacific Journal of Clinical Nutrition 02/2004; 13(3):273-83. · 1.13 Impact Factor
