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1.  A Rank-Based Test for Comparison of Multidimensional Outcomes 
For comparison of multiple outcomes commonly encountered in biomedical research, Huang et al. (2005) improved O’Brien’s (1984) rank-sum tests through the replacement of the ad hoc variance by the asymptotic variance of the test statistics. The improved tests control the Type I error rate at the desired level and gain power when the differences between the two comparison groups in each outcome variable fall into the same direction. However, they may lose power when the differences are in different directions (e.g., some are positive and some are negative). These tests and the popular Bonferroni correction failed to show important significant difference when applied to compare heart rates from a clinical trial to evaluate the effect of a procedure to remove the cardioprotective solution HTK. We propose an alternative test statistic, taking the maximum of the individual rank-sum statistics, which controls the type I error and maintains satisfactory power regardless of the directions of the differences. Simulation studies show the proposed test to be of higher power than other tests in certain alternative parameter space of interest. Furthermore, when used to analyze the heart rates data the proposed test yields more satisfactory results.
doi:10.1198/jasa.2010.ap09114
PMCID: PMC3102319  PMID: 21625372
Autism spectrum disorder; Behrens-Fisher problem; Cardioprotective solution; Case-control studies; Growth hormones; Multiple outcomes; Non-parametrics; Rank-sum statistics
2.  A Weighted Rank-Sum Procedure for Comparing Samples with Multiple Endpoints 
Statistics and its interface  2009;2(2):197-201.
Summary
For comparing the distribution of two samples with multiple endpoints, O’Brien (1984) proposed rank-sum-type test statistics. Huang et al. (2005) extended these statistics to the general nonparametric Behrens-Fisher hypothesis problem and obtained improved test statistics by replacing the ad hoc variance with the asymptotic variance of the rank-sum statistics. In this paper we generalize the work of O’Brien (1984) and Huang et al. (2005) and propose a weighted rank-sum statistic. We show that the weighted rank-sum statistic is asymptotically normally distributed, permitting the computation of power, p-values and confidence intervals. We further demonstrate via simulation that the weighted rank-sum statistic is efficient in controlling the type I error rate and under certain alternatives, is more powerful than the statistics of O’Brien (1984) and Huang et al.(2005).
PMCID: PMC2759535  PMID: 19823699
Asymptotic normality; Behrens-Fisher problem; Case-Control; Clinical trials; Multiple endpoints; Rank-sum statistics; Weights
3.  A fast and powerful tree-based association test for detecting complex joint effects in case–control studies 
Bioinformatics  2014;30(15):2171-2178.
Motivation: Multivariate tests derived from the logistic regression model are widely used to assess the joint effect of multiple predictors on a disease outcome in case–control studies. These tests become less optimal if the joint effect cannot be approximated adequately by the additive model. The tree-structure model is an attractive alternative, as it is more apt to capture non-additive effects. However, the tree model is used most commonly for prediction and seldom for hypothesis testing, mainly because of the computational burden associated with the resampling-based procedure required for estimating the significance level.
Results: We designed a fast algorithm for building the tree-structure model and proposed a robust TREe-based Association Test (TREAT) that incorporates an adaptive model selection procedure to identify the optimal tree model representing the joint effect. We applied TREAT as a multilocus association test on >20 000 genes/regions in a study of esophageal squamous cell carcinoma (ESCC) and detected a highly significant novel association between the gene CDKN2B and ESCC (). We also demonstrated, through simulation studies, the power advantage of TREAT over other commonly used tests.
Availability and implementation: The package TREAT is freely available for download at http://www.hanzhang.name/softwares/treat, implemented in C++ and R and supported on 64-bit Linux and 64-bit MS Windows.
Contact:  yuka@mail.nih.gov
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu186
PMCID: PMC4103596  PMID: 24794927
4.  Cutting improves the productivity of lucerne-rich stands used in the revegetation of degraded arable land in a semi-arid environment 
Scientific Reports  2015;5:12130.
Understanding the relationships between vegetative and environmental variables is important for revegetation and ecosystem management on the Loess Plateau, China. Lucerne (Medicago sativa L.) has been widely used in the region to improve revegetation, soil and water conservation, and to enhance livestock production. However, there is little information on how environmental factors influence long-term succession in lucerne-rich vegetation. Our objective was to identify the main environmental variables controlling the succession process in lucerne-rich vegetation such that native species are not suppressed after sowing on the Loess Plateau. Vegetation and soil surveys were performed in 31 lucerne fields (three lucerne fields without any management from 2003–2013 and 28 fields containing 11-year-old lucerne with one cutting each year). Time after planting was the most important factor affecting plant species succession. Cutting significantly affected revegetation characteristics, such as aboveground biomass, plant density and diversity. Soil moisture content, soil organic carbon, soil available phosphorus and slope aspect were key environmental factors affecting plant species composition and aboveground biomass, density and diversity. Long-term cutting can cause self-thinning in lucerne, maintain the stability of lucerne production and slow its degradation. For effective management of lucerne fields, phosphate fertilizer should be applied and cutting performed.
doi:10.1038/srep12130
PMCID: PMC4499809  PMID: 26166449
5.  ErbB4 regulation of a thalamic reticular nucleus circuit for sensory selection 
Nature neuroscience  2014;18(1):104-111.
Selective processing of behaviorally relevant sensory inputs against irrelevant ones is a fundamental cognitive function, impairments of which have been implicated in major psychiatric disorders. It is known that the thalamic reticular nucleus (TRN) gates sensory information en route to the cortex, however the underlying mechanisms remain unclear. Here we show in mice that deficiency of Erbb4 gene in somatostatin-expressing TRN neurons markedly altered behaviors dependent on sensory selection. Whereas performance in identifying targets from distractors was improved, the ability to switch attention between conflicting sensory cues was impaired. These behavioral changes were mediated by enhanced cortical drive onto TRN that promotes the TRN-mediated cortical feedback inhibition of thalamic neurons. Our results uncover a previously unknown role of ErbB4 in regulating cortico-TRN-thalamic circuit function. We propose that ErbB4 sets the sensitivity of TRN to cortical inputs at levels that can support sensory selection while allowing behavioral flexibility.
doi:10.1038/nn.3897
PMCID: PMC4281280  PMID: 25501036
6.  Characterization of SMAD3 Gene Variants for Possible Roles in Ventricular Septal Defects and Other Congenital Heart Diseases 
PLoS ONE  2015;10(6):e0131542.
Background
Nodal/TGF signaling pathway has an important effect at early stages of differentiation of human embryonic stem cells in directing them to develop into different embryonic lineages. SMAD3 is a key intracellular messenger regulating factor in the Nodal/TGF signaling pathway, playing important roles in embryonic and, particularly, cardiovascular system development. The aim of this work was to find evidence on whether SMAD3 variations might be associated with ventricular septal defects (VSD) or other congenital heart diseases (CHD).
Methods
We sequenced the SMAD3 gene for 372 Chinese Han CHD patients including 176 VSD patients and evaluated SNP rs2289263, which is located before the 5’UTR sequence of the gene. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0). The Hardy-Weinberg equilibrium test of the population was carried out using the online software OEGE.
Results
Three heterozygous variants in SMAD3 gene, rs2289263, rs35874463 and rs17228212, were identified. Statistical analyses showed that the rs2289263 variant located before the 5’UTR sequence of SMAD3 gene was associated with the risk of VSD (P value=0.013 <0.05).
Conclusions
The SNP rs2289263 in the SMAD3 gene is associated with VSD in Chinese Han populations.
doi:10.1371/journal.pone.0131542
PMCID: PMC4482402  PMID: 26110764
8.  Variants Associated with Susceptibility to Pancreatic Cancer and Melanoma Do Not Reciprocally Affect Risk 
Background
Melanoma cases may exist in pancreatic cancer kindreds, while there is increased risk of pancreatic cancer in familial melanoma. The two cancers may share genetic susceptibility variants in common.
Methods
Three dbGaP-deposited GWAS datasets (MD Anderson melanoma, PanScan 1, and PanScan 2 for pancreatic cancer) were used. Thirty-seven melanoma susceptibility variants in 22 genomic regions from published GWAS, plus melanoma-related genes and pathways were examined for pancreatic cancer risk in the PanScan datasets. Conversely, nine known pancreatic cancer susceptibility variants were examined for melanoma risk in the MD Anderson dataset.
Results
In the PanScan data, initial associations were found with melanoma susceptibility variants in NCOA6 (rs4911442) (OR=1.32, 95% CI 1.03–1.70, p=0.03), YWHAZP5 (rs17119461) (OR=2.62, 95% CI 1.08–6.35, p=0.03), and YWHAZP5 (rs17119490) (OR=2.62, 95% CI 1.08–6.34, p=0.03), TYRP1 (p=0.04), and IFNA13 (p=0.04). In the melanoma dataset, two pancreatic cancer susceptibility variants were associated: NR5A2 (rs12029406) (OR=1.39, 95% CI 1.01–1.92, p=0.04) and CLPTM1L-TERT (rs401681) (OR=1.16, 95% CI 1.01–1.34, p=0.04). None of these associations remained significant after correcting for multiple comparisons.
Conclusion
Reported variants of melanoma genes and pathways do not play a role in pancreatic cancer predisposition. Reciprocally, pancreatic cancer susceptibility variants are not associated with melanoma risk.
Impact
Known melanoma-related genes and pathways, as well as GWAS-derived susceptibility variants of melanoma and pancreatic cancer, do not explain the shared genetic etiology of these two cancers.
doi:10.1158/1055-9965.EPI-13-0627
PMCID: PMC4120837  PMID: 24642353
Shared etiology; pancreatic cancer; melanoma; association analysis
9.  Sequential blood purification therapy for critical patients with hyperlipidemic severe acute pancreatitis 
AIM: To evaluate the efficacy of sequential blood purification therapy in the treatment of critical patients with hyperlipidemic severe acute pancreatitis.
METHODS: Thirty-one intensive care unit (ICU) patients with hyperlipidemic severe acute pancreatitis treated at the Second Affiliated Hospital of Harbin Medical University were divided into either a study group (n = 15; July 1, 2012 to June 30, 2014) or a control group (n = 16; July 1, 2010 to June 30, 2012) based on the implementation of sequential blood purification therapy. The control group received continuous venous-venous hemofiltration (CVVH) on the basis of conventional treatments, and the therapeutic dose of CVVH was 30 mL/kg per hour. The study group received sequential plasma exchange and CVVH on the basis of conventional treatments. The anticoagulation regimen of CVVH is the regional citrate anticoagulation. Mortality rate on day 28, rates of systemic and local complications, duration of ICU, and time to target serum lipid level, as well as physiologic and laboratory indices were compared between the two groups.
RESULTS: The mortality rate on day 28 was significantly lower in the study group than in the control group (13.33% vs 37.50%; P < 0.05). The duration of ICU stay was significantly shorter in the study group than in the control group (7.4 ± 1.35 d vs 9.19 ± 2.99 d, P < 0.05). The time to target serum lipid level was significantly shorter in the study group than in the control group (3.47 ± 0.52 d vs 7.90 ± 1.14 d, P < 0.01). There were no significant differences in the rates of systemic complications and local complications between the two groups (60% vs 50% and 80% vs 81%, respectively). In the comparisons of physiologic and laboratory indices, serum albumin and C-reactive protein were significantly better in the study group than in the control group after treatment (37.8 ± 4.6 g/L vs 38.9 ± 5.7 g/L, and 20.5 ± 6.4 mg/L vs 28.5 ± 7.1 mg/L, respectively, both P < 0.05). With the exception of plateletcrit, no other indices showed significant differences between the two groups.
CONCLUSION: Sequential blood purification therapy is effective in the treatment of ICU patients with hyperlipidemic severe acute pancreatitis and can improve patient prognosis.
doi:10.3748/wjg.v21.i20.6304
PMCID: PMC4445108  PMID: 26034366
Continuous venous-venous hemofiltration; Hyperlipidemic severe acute pancreatitis; Sequential blood purification; Plasma exchange
10.  A genome-wide association study of prostate cancer in West African men 
Human genetics  2013;133(5):509-521.
Background
Age-adjusted mortality rates for prostate cancer are higher for African American men compared with those of European ancestry. Recent data suggest that West African men also have elevated risk for prostate cancer relative to European men. Genetic susceptibility to prostate cancer could account for part of this difference.
Methods
We conducted a genome-wide association study (GWAS) of prostate cancer in West African men in the Ghana Prostate Study. Association testing was performed using multivariable logistic regression adjusted for age and genetic ancestry for 474 prostate cancer cases and 458 population-based controls on the Illumina HumanOmni-5 Quad BeadChip.
Results
The most promising association was at 10p14 within an intron of a long non-coding RNA (lncRNA RP11-543F8.2) 360 kb centromeric of GATA3 (p=1.29E−7). In sub-analyses, SNPs at 5q31.3 were associated with high Gleason score (≥7) cancers, the strongest of which was a missense SNP in PCDHA1 (rs34575154, p=3.66E−8), and SNPs at Xq28 (rs985081, p=8.66E−9) and 6q21 (rs2185710, p=5.95E−8) were associated with low Gleason score (<7) cancers. We sought to validate our findings in silico in the African Ancestry Prostate Cancer GWAS Consortium, but only one SNP, at 10p14, replicated at p<0.05. Of the 90 prostate cancer loci reported from studies of men of European, Asian or African American ancestry, we were able to test 81 in the Ghana Prostate Study, and 10 of these replicated at p<0.05.
Conclusion
Further genetic studies of prostate cancer in West African men are needed to confirm our promising susceptibility loci.
doi:10.1007/s00439-013-1387-z
PMCID: PMC3988225  PMID: 24185611
prostate cancer; Africa; GWAS; case-control
11.  A fast multilocus test with adaptive SNP selection for large-scale genetic-association studies 
As increasing evidence suggests that multiple correlated genetic variants could jointly influence the outcome, a multilocus test that aggregates association evidence across multiple genetic markers in a considered gene or a genomic region may be more powerful than a single-marker test for detecting susceptibility loci. We propose a multilocus test, AdaJoint, which adopts a variable selection procedure to identify a subset of genetic markers that jointly show the strongest association signal, and defines the test statistic based on the selected genetic markers. The P-value from the AdaJoint test is evaluated by a computationally efficient algorithm that effectively adjusts for multiple-comparison, and is hundreds of times faster than the standard permutation method. Simulation studies demonstrate that AdaJoint has the most robust performance among several commonly used multilocus tests. We perform multilocus analysis of over 26 000 genes/regions on two genome-wide association studies of pancreatic cancer. Compared with its competitors, AdaJoint identifies a much stronger association between the gene CLPTM1L and pancreatic cancer risk (6.0 × 10−8), with the signal optimally captured by two correlated single-nucleotide polymorphisms (SNPs). Finally, we show AdaJoint as a powerful tool for mapping cis-regulating methylation quantitative trait loci on normal breast tissues, and find many CpG sites whose methylation levels are jointly regulated by multiple SNPs nearby.
doi:10.1038/ejhg.2013.201
PMCID: PMC3992564  PMID: 24022295
genome-wide association study; cis-regulating meQTLs mapping; multilocus test; variable selection; multiple comparisons; pathway analysis
12.  A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer 
Al Olama, Ali Amin | Kote-Jarai, Zsofia | Berndt, Sonja I. | Conti, David V. | Schumacher, Fredrick | Han, Ying | Benlloch, Sara | Hazelett, Dennis J. | Wang, Zhaoming | Saunders, Ed | Leongamornlert, Daniel | Lindstrom, Sara | Jugurnauth-Little, Sara | Dadaev, Tokhir | Tymrakiewicz, Malgorzata | Stram, Daniel O. | Rand, Kristin | Wan, Peggy | Stram, Alex | Sheng, Xin | Pooler, Loreall C. | Park, Karen | Xia, Lucy | Tyrer, Jonathan | Kolonel, Laurence N. | Le Marchand, Loic | Hoover, Robert N. | Machiela, Mitchell J. | Yeager, Merideth | Burdette, Laurie | Chung, Charles C. | Hutchinson, Amy | Yu, Kai | Goh, Chee | Ahmed, Mahbubl | Govindasami, Koveela | Guy, Michelle | Tammela, Teuvo L.J. | Auvinen, Anssi | Wahlfors, Tiina | Schleutker, Johanna | Visakorpi, Tapio | Leinonen, Katri A. | Xu, Jianfeng | Aly, Markus | Donovan, Jenny | Travis, Ruth C. | Key, Tim J. | Siddiq, Afshan | Canzian, Federico | Khaw, Kay-Tee | Takahashi, Atsushi | Kubo, Michiaki | Pharoah, Paul | Pashayan, Nora | Weischer, Maren | Nordestgaard, Borge G. | Nielsen, Sune F. | Klarskov, Peter | Røder, Martin Andreas | Iversen, Peter | Thibodeau, Stephen N. | McDonnell, Shannon K | Schaid, Daniel J | Stanford, Janet L. | Kolb, Suzanne | Holt, Sarah | Knudsen, Beatrice | Coll, Antonio Hurtado | Gapstur, Susan M. | Diver, W. Ryan | Stevens, Victoria L. | Maier, Christiane | Luedeke, Manuel | Herkommer, Kathleen | Rinckleb, Antje E. | Strom, Sara S. | Pettaway, Curtis | Yeboah, Edward D. | Tettey, Yao | Biritwum, Richard B. | Adjei, Andrew A. | Tay, Evelyn | Truelove, Ann | Niwa, Shelley | Chokkalingam, Anand P. | Cannon-Albright, Lisa | Cybulski, Cezary | Wokołorczyk, Dominika | Kluźniak, Wojciech | Park, Jong | Sellers, Thomas | Lin, Hui-Yi | Isaacs, William B. | Partin, Alan W. | Brenner, Hermann | Dieffenbach, Aida Karina | Stegmaier, Christa | Chen, Constance | Giovannucci, Edward L. | Ma, Jing | Stampfer, Meir | Penney, Kathryn L. | Mucci, Lorelei | John, Esther M. | Ingles, Sue A. | Kittles, Rick A. | Murphy, Adam B. | Pandha, Hardev | Michael, Agnieszka | Kierzek, Andrzej M. | Blot, William | Signorello, Lisa B. | Zheng, Wei | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Nemesure, Barbara | Carpten, John | Leske, Cristina | Wu, Suh-Yuh | Hennis, Anselm | Kibel, Adam S. | Rybicki, Benjamin A. | Neslund-Dudas, Christine | Hsing, Ann W. | Chu, Lisa | Goodman, Phyllis J. | Klein, Eric A | Zheng, S. Lilly | Batra, Jyotsna | Clements, Judith | Spurdle, Amanda | Teixeira, Manuel R. | Paulo, Paula | Maia, Sofia | Slavov, Chavdar | Kaneva, Radka | Mitev, Vanio | Witte, John S. | Casey, Graham | Gillanders, Elizabeth M. | Seminara, Daniella | Riboli, Elio | Hamdy, Freddie C. | Coetzee, Gerhard A. | Li, Qiyuan | Freedman, Matthew L. | Hunter, David J. | Muir, Kenneth | Gronberg, Henrik | Neal, David E. | Southey, Melissa | Giles, Graham G. | Severi, Gianluca | Cook, Michael B. | Nakagawa, Hidewaki | Wiklund, Fredrik | Kraft, Peter | Chanock, Stephen J. | Henderson, Brian E. | Easton, Douglas F. | Eeles, Rosalind A. | Haiman, Christopher A.
Nature genetics  2014;46(10):1103-1109.
Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of >10 million SNPs in 43,303prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three novel susceptibility loci were revealed at P<5×10-8; 15 variants were identified among men of European ancestry, 7 from multiethnic analyses and one was associated with early-onset prostate cancer. These 23 variants, in combination with the known prostate cancer risk variants, explain 33% of the familial risk of the disease in European ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the utility of combining ancestrally diverse populations to discover risk loci for disease.
doi:10.1038/ng.3094
PMCID: PMC4383163  PMID: 25217961
13.  Vitamin D Metabolic Pathway Genes and Pancreatic Cancer Risk 
PLoS ONE  2015;10(3):e0117574.
Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008–0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk.
doi:10.1371/journal.pone.0117574
PMCID: PMC4370655  PMID: 25799011
14.  CD44 family proteins in gastric cancer: a meta-analysis and narrative review 
With a meta-analysis and narrative review, we evaluated the clinical and prognostic role of all CD44 family proteins in gastric cancer (GC). Literatures published up to August 2014 were searched on PubMed. Among the 37 eligible studies (6606 patients), 34 were included in meta-analysis, and 10 were subjected to narrative review. With meta-analysis, standard CD44 (CD44s) was demonstrated to predict reduced overall survival (OS) (HR = 1.93, 95% CI: 1.58-2.34, PHR = 0.0222) and disease free survival (HR = 3.13, 95% CI: 1.02-9.68, PHR = 0.0469), advanced N-stage (RR = 1.12, 95% CI: 1.04-1.21, PRR = 0.0019), and distant metastasis (RR = 2.14, 95% CI: 1.46-3.14, PRR < 0.0001) of GC. CD44 variant 6 (CD44v6) in GC might influence OS (5 studies; HR = 1.27, 95% CI: 0.75-2.14, PHR = 0.3783; 4 studies; HR = 1.52, 95% CI: 1.09-2.14, PHR = 0.0139), while significantly associated with N-stage (RR = 1.23, 95% CI: 1.03-1.48, PRR = 0.0240), M-stage (RR = 2.54, 95% CI: 1.08-6.00, PRR = 0.0333), TNM-stage (RR = 1.72, 95% CI: 1.18-2.50, PRR = 0.0045), Lauren type (RR = 0.67, 95% CI: 0.50-0.91, PRR = 0.0106), lymphatic invasion (RR = 1.13, 95% CI: 1.04-1.23, PRR = 0.0057), and liver metastasis (RR = 3.20, 95% CI: 1.94-5.27, PRR < 0.0001) of the disease. Moreover, a narrative review was performed for CD44 isoforms, such as v3, v5, v7, v8-10, and v9, in GC. In conclusion, CD44s and CD44v6 as evaluated by immunohistochemistry, respectively, predicts the prognosis and disease severity of GC.
PMCID: PMC4443089  PMID: 26064255
CD44s; CD44 variants; gastric cancer; meta-analysis; narrative review; prognosis
15.  Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer 
Wolpin, Brian M. | Rizzato, Cosmeri | Kraft, Peter | Kooperberg, Charles | Petersen, Gloria M. | Wang, Zhaoming | Arslan, Alan A. | Beane-Freeman, Laura | Bracci, Paige M. | Buring, Julie | Canzian, Federico | Duell, Eric J. | Gallinger, Steven | Giles, Graham G. | Goodman, Gary E. | Goodman, Phyllis J. | Jacobs, Eric J. | Kamineni, Aruna | Klein, Alison P. | Kolonel, Laurence N. | Kulke, Matthew H. | Li, Donghui | Malats, Núria | Olson, Sara H. | Risch, Harvey A. | Sesso, Howard D. | Visvanathan, Kala | White, Emily | Zheng, Wei | Abnet, Christian C. | Albanes, Demetrius | Andreotti, Gabriella | Austin, Melissa A. | Barfield, Richard | Basso, Daniela | Berndt, Sonja I. | Boutron-Ruault, Marie-Christine | Brotzman, Michelle | Büchler, Markus W. | Bueno-de-Mesquita, H. Bas | Bugert, Peter | Burdette, Laurie | Campa, Daniele | Caporaso, Neil E. | Capurso, Gabriele | Chung, Charles | Cotterchio, Michelle | Costello, Eithne | Elena, Joanne | Funel, Niccola | Gaziano, J. Michael | Giese, Nathalia A. | Giovannucci, Edward L. | Goggins, Michael | Gorman, Megan J. | Gross, Myron | Haiman, Christopher A. | Hassan, Manal | Helzlsouer, Kathy J. | Henderson, Brian E. | Holly, Elizabeth A. | Hu, Nan | Hunter, David J. | Innocenti, Federico | Jenab, Mazda | Kaaks, Rudolf | Key, Timothy J. | Khaw, Kay-Tee | Klein, Eric A. | Kogevinas, Manolis | Krogh, Vittorio | Kupcinskas, Juozas | Kurtz, Robert C. | LaCroix, Andrea | Landi, Maria T. | Landi, Stefano | Le Marchand, Loic | Mambrini, Andrea | Mannisto, Satu | Milne, Roger L. | Nakamura, Yusuke | Oberg, Ann L. | Owzar, Kouros | Patel, Alpa V. | Peeters, Petra H. M. | Peters, Ulrike | Pezzilli, Raffaele | Piepoli, Ada | Porta, Miquel | Real, Francisco X. | Riboli, Elio | Rothman, Nathaniel | Scarpa, Aldo | Shu, Xiao-Ou | Silverman, Debra T. | Soucek, Pavel | Sund, Malin | Talar-Wojnarowska, Renata | Taylor, Philip R. | Theodoropoulos, George E. | Thornquist, Mark | Tjønneland, Anne | Tobias, Geoffrey S. | Trichopoulos, Dimitrios | Vodicka, Pavel | Wactawski-Wende, Jean | Wentzensen, Nicolas | Wu, Chen | Yu, Herbert | Yu, Kai | Zeleniuch-Jacquotte, Anne | Hoover, Robert | Hartge, Patricia | Fuchs, Charles | Chanock, Stephen J. | Stolzenberg-Solomon, Rachael S. | Amundadottir, Laufey T.
Nature genetics  2014;46(9):994-1000.
We performed a multistage genome-wide association study (GWAS) including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT; per-allele odds ratio [OR] = 0.79; 95% confidence interval [CI] = 0.74–0.84; P = 3.0×10−12), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2; OR = 1.46; 95% CI = 1.30–1.65; P = 1.1×10−10), rs9581943 at 13q12.2 (PDX1; OR = 1.15; 95% CI = 1.10–1.20; P = 2.4×10−9), and rs16986825 at 22q12.1 (ZNRF3; OR = 1.18; 95% CI = 1.12–1.25; P = 1.2×10−8). An independent signal was identified in exon 2 of TERT at the established region 5p15.33 (rs2736098; OR = 0.80; 95% CI = 0.76–0.85; P = 9.8×10−14). We also identified a locus at 8q24.21 (rs1561927; P = 1.3×10−7) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study has identified multiple new susceptibility alleles for pancreatic cancer worthy of follow-up studies.
doi:10.1038/ng.3052
PMCID: PMC4191666  PMID: 25086665
16.  Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations 
Wu, Chen | Wang, Zhaoming | Song, Xin | Feng, Xiao-Shan | Abnet, Christian C. | He, Jie | Hu, Nan | Zuo, Xian-Bo | Tan, Wen | Zhan, Qimin | Hu, Zhibin | He, Zhonghu | Jia, Weihua | Zhou, Yifeng | Yu, Kai | Shu, Xiao-Ou | Yuan, Jian-Min | Zheng, Wei | Zhao, Xue-Ke | Gao, She-Gan | Yuan, Zhi-Qing | Zhou, Fu-You | Fan, Zong-Min | Cui, Ji-Li | Lin, Hong-Li | Han, Xue-Na | Li, Bei | Chen, Xi | Dawsey, Sanford M. | Liao, Linda | Lee, Maxwell P. | Ding, Ti | Qiao, You-Lin | Liu, Zhihua | Liu, Yu | Yu, Dianke | Chang, Jiang | Wei, Lixuan | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Han, Jing-Jing | Zhou, Sheng-Li | Zhang, Peng | Zhang, Dong-Yun | Yuan, Yuan | Huang, Ying | Liu, Chunling | Zhai, Kan | Qiao, Yan | Jin, Guangfu | Guo, Chuanhai | Fu, Jianhua | Miao, Xiaoping | Lu, Changdong | Yang, Haijun | Wang, Chaoyu | Wheeler, William A. | Gail, Mitchell | Yeager, Meredith | Yuenger, Jeff | Guo, Er-Tao | Li, Ai-Li | Zhang, Wei | Li, Xue-Min | Sun, Liang-Dan | Ma, Bao-Gen | Li, Yan | Tang, Sa | Peng, Xiu-Qing | Liu, Jing | Hutchinson, Amy | Jacobs, Kevin | Giffen, Carol | Burdette, Laurie | Fraumeni, Joseph F. | Shen, Hongbing | Ke, Yang | Zeng, Yixin | Wu, Tangchun | Kraft, Peter | Chung, Charles C. | Tucker, Margaret A. | Hou, Zhi-Chao | Liu, Ya-Li | Hu, Yan-Long | Liu, Yu | Wang, Li | Yuan, Guo | Chen, Li-Sha | Liu, Xiao | Ma, Teng | Meng, Hui | Sun, Li | Li, Xin-Min | Li, Xiu-Min | Ku, Jian-Wei | Zhou, Ying-Fa | Yang, Liu-Qin | Wang, Zhou | Li, Yin | Qige, Qirenwang | Yang, Wen-Jun | Lei, Guang-Yan | Chen, Long-Qi | Li, En-Min | Yuan, Ling | Yue, Wen-Bin | Wang, Ran | Wang, Lu-Wen | Fan, Xue-Ping | Zhu, Fang-Heng | Zhao, Wei-Xing | Mao, Yi-Min | Zhang, Mei | Xing, Guo-Lan | Li, Ji-Lin | Han, Min | Ren, Jing-Li | Liu, Bin | Ren, Shu-Wei | Kong, Qing-Peng | Li, Feng | Sheyhidin, Ilyar | Wei, Wu | Zhang, Yan-Rui | Feng, Chang-Wei | Wang, Jin | Yang, Yu-Hua | Hao, Hong-Zhang | Bao, Qi-De | Liu, Bao-Chi | Wu, Ai-Qun | Xie, Dong | Yang, Wan-Cai | Wang, Liang | Zhao, Xiao-Hang | Chen, Shu-Qing | Hong, Jun-Yan | Zhang, Xue-Jun | Freedman, Neal D | Goldstein, Alisa M. | Lin, Dongxin | Taylor, Philip R. | Wang, Li-Dong | Chanock, Stephen J.
Nature genetics  2014;46(9):1001-1006.
We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) 1-3 of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10−20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10−13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10−10). Our joint analysis identified new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region.
doi:10.1038/ng.3064
PMCID: PMC4212832  PMID: 25129146
17.  High Prevalence of Screen Detected Prostate Cancer in West Africans: Implications for Racial Disparity of Prostate Cancer 
The Journal of urology  2014;192(3):730-735.
Purpose
To our knowledge the reasons for the high rates of prostate cancer in black American men are unknown. Genetic and lifestyle factors have been implicated. Better understanding of prostate cancer rates in West African men would help clarify why black American men have such high rates since the groups share genetic ancestry and yet have different lifestyles and screening practices. To estimate the prostate cancer burden in West African men we performed a population based screening study with biopsy confirmation in Ghana.
Materials and Methods
We randomly selected 1,037 healthy men 50 to 74 years old from Accra, Ghana for prostate cancer screening with prostate specific antigen testing and digital rectal examination. Men with a positive screen result (positive digital rectal examination or prostate specific antigen greater than 2.5 ng/ml) underwent transrectal ultrasound guided biopsies.
Results
Of the 1,037 men 154 (14.9%) had a positive digital rectal examination and 272 (26.2%) had prostate specific antigen greater than 2.5 ng/ml, including 166 with prostate specific antigen greater than 4.0 ng/ml. A total of 352 men (33.9%) had a positive screen by prostate specific antigen or digital rectal examination and 307 (87%) underwent biopsy. Of these men 73 were confirmed to have prostate cancer, yielding a 7.0% screen detected prostate cancer prevalence (65 patients), including 5.8% with prostate specific antigen greater than 4.0 ng/ml.
Conclusions
In this relatively unscreened population in Africa the screen detected prostate cancer prevalence is high, suggesting a possible role of genetics in prostate cancer etiology and the disparity in prostate cancer risk between black and white American men. Further studies are needed to confirm the high prostate cancer burden in African men and the role of genetics in prostate cancer etiology.
doi:10.1016/j.juro.2014.04.017
PMCID: PMC4332806  PMID: 24747091
prostatic neoplasms; prostate-specific antigen; mass screening; African Americans; Africa
18.  Genetic variants in Fas signaling pathway genes and risk of gastric cancer 
Populations in north central China are at high risk for gastric cancers (GC), and altered FAS-mediated cell signaling and/or apoptosis may contribute to this risk. We examined the association of 554 single nucleotide polymorphisms (SNPs) in 53 Fas signaling-related genes using a pathway-based approach in 1758 GC cases (1126 gastric cardia adenocarcinomas (GCA) and 632 gastric noncardia adenocarcinomas (GNCA)), and 2111 controls from a genome-wide association study (GWAS) of GC in ethnic Chinese. SNP associations with risk of overall GC, GCA and GNCA were evaluated using unconditional logistic regressions controlling for age, sex and study. Gene- and pathway-based associations were tested using the adaptive rank-truncated product (ARTP) method. Statistical significance was evaluated empirically by permutation. Significant pathway-based associations were observed for Fas signaling with risk of overall GC (P = 5.5E-04) and GCA (P = 6.3E-03), but not GNCA (P = 8.1E-02). Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2 and IKBKB were associated with risk of GC (nominal P < 0.05), and FAF1 and MAPK8 were significantly associated with risk of both GCA and GNCA (nominal P < 0.05). Our examination of genetic variation in the Fas signaling pathway is consistent with an association of altered Fas signaling and/or apoptosis with risk of GC. As one of the first attempts to investigate a pathway-level association, our results suggest that these genes and the Fas signaling pathway warrant further evaluation in relation to GC risk in other populations.
doi:10.1002/ijc.28415
PMCID: PMC3858487  PMID: 23921907
Gastric cancer; gastric cardia; gastric noncardia; Fas signaling; genetic variants; GWAS; single nucleotide polymorphisms; pathway genes
19.  Effects of Glucagon-Like Peptide-1 Receptor Agonists on Weight Loss in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis 
Journal of Diabetes Research  2015;2015:157201.
To evaluate the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on weight reduction in patients with Type 2 diabetes mellitus (Type 2 DM), a network meta-analysis was conducted. MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched from 1950 to October 2013. Randomized controlled trials (RCTs) involving GLP-1 RAs were included if they provided information on body weight. A total of 51 RCTs were included and 17521 participants were enrolled. The mean duration of 51 RCTs was 31 weeks. Exenatide 10 μg twice daily (EX10BID) reduced weight compared with exenatide 5 μg twice daily (EX5BID), liraglutide 0.6 mg once daily (LIR0.6QD), liraglutide—1.2 mg once daily (LIR1.2QD), and placebo treatment, with mean differences of −1.07 kg (95% CI: −2.41, −0.02), −2.38 kg (95% CI: −3.71, −1.06), −1.62 kg (95% CI: −2.79, −0.43), and −1.92 kg (95% CI: −2.61, −1.24), respectively. Reductions of weight treated with liraglutide—1.8 mg once daily (LIR1.8QD) reach statistical significance (−1.43 kg (95% CI: −2.73, −0.15)) versus LIR1.2QD and (−0.98 kg (95% CI: −1.94, −0.02)) versus placebo. Network meta-analysis found that EX10BID, LIR1.8QD, and EX2QW obtained a higher proportion of patients with weight loss than other traditional hypoglycemic agents. Our results suggest GLP-1 RAs are promising candidates for weight control in comparison with traditional hypoglycemic drugs, and EX10BID, LIR1.8QD, and EX2QW rank the top three drugs.
doi:10.1155/2015/157201
PMCID: PMC4320855  PMID: 25688373
20.  Non-invasive evaluation of therapeutic response in keloid scar using diffuse reflectance spectroscopy 
Biomedical Optics Express  2015;6(2):390-404.
The pathogenesis and ideal treatment of keloid are still largely unknown, and it is essential to develop an objective assessment of keloid severity to evaluate the therapeutic response. We previously reported that our diffuse reflectance spectroscopy (DRS) system could assist clinicians in understanding the functional and structural condition of keloid scars. The purpose of this study was to understand clinical applicability of our DRS system on evaluating the scar severity and therapeutic response of keloid. We analyzed 228 spectral data from 71 subjects with keloid scars. The scars were classified into mild (0-3), moderate (4-7) and severe (8-11) according to the Vancouver scar scale. We found that as the severity of the scar increased, collagen concentration and water content increased, and the reduced scattering coefficient at 800 nm and oxygen saturation (SaO2) decreased. Using the DRS system, we found that collagen bundles aligned in a specific direction in keloid scars, but not in normal scars. Water content and SaO2 may be utilized as reliable parameters for evaluating the therapeutic response of keloid. In conclusion, the results obtained here suggest that the DRS has potential as an objective technique with which to evaluate keloid scar severity. In addition, it may be useful as a tool with which to track longitudinal response of scars in response to various therapeutic interventions.
doi:10.1364/BOE.6.000390
PMCID: PMC4354586  PMID: 25780731
(170.5280) Photon migration; (170.4580) Optical diagnostics for medicine; (170.6510) Spectroscopy, tissue diagnostics; (290.1990) Diffusion
21.  Comparing Miniopen and Minimally Invasive Transforaminal Interbody Fusion in Single-Level Lumbar Degeneration 
BioMed Research International  2015;2015:168384.
Degenerative diseases of the lumbar spine, which are common among elderly people, cause back pain and radicular symptoms and lead to a poor quality of life. Lumbar spinal fusion is a standardized and widely accepted surgical procedure used for treating degenerative lumbar diseases; however, the classical posterior approach used in this procedure is recognized to cause vascular and neurologic damage of the lumbar muscles. Various studies have suggested that using the minimally invasive transforaminal interbody fusion (TLIF) technique provides long-term clinical outcomes comparable to those of open TLIF approaches in selected patients. In this study, we compared the perioperative and short-term advantages of miniopen, MI, and open TLIF. Compared with open TLIF, MI-TLIF and miniopen TLIF were associated with less blood loss, shorter hospital stays, and longer operative times; however, following the use of these procedures, no difference in quality of life was measured at 6 months or 1 year. Whether miniopen TLIF or MI-TLIF can replace traditional TLIF as the surgery of choice for treating degenerative lumbar deformity remains unclear, and additional studies are required for validating the safety and efficiency of these procedures.
doi:10.1155/2015/168384
PMCID: PMC4299488  PMID: 25629037
22.  Antecedent acute cycling exercise affects attention control: an ERP study using attention network test 
The purpose of this study was to investigate the after-effects of an acute bout of moderate intensity aerobic cycling exercise on neuroelectric and behavioral indices of efficiency of three attentional networks: alerting, orienting, and executive (conflict) control. Thirty young, highly fit amateur basketball players performed a multifunctional attentional reaction time task, the attention network test (ANT), with a two-group randomized experimental design after an acute bout of moderate intensity spinning wheel exercise or without antecedent exercise. The ANT combined warning signals prior to targets, spatial cueing of potential target locations and target stimuli surrounded by congruent or incongruent flankers, which were provided to assess three attentional networks. Event-related brain potentials and task performance were measured during the ANT. Exercise resulted in a larger P3 amplitude in the alerting and executive control subtasks across frontal, central and parietal midline sites that was paralleled by an enhanced reaction speed only on trials with incongruent flankers of the executive control network. The P3 latency and response accuracy were not affected by exercise. These findings suggest that after spinning, more resources are allocated to task-relevant stimuli in tasks that rely on the alerting and executive control networks. However, the improvement in performance was observed in only the executively challenging conflict condition, suggesting that whether the brain resources that are rendered available immediately after acute exercise translate into better attention performance depends on the cognitive task complexity.
doi:10.3389/fnhum.2015.00156
PMCID: PMC4391039  PMID: 25914634
alerting; orienting; executive function; interference control; spinning
23.  Synchronous poorly-differentiated neuroendocrine carcinoma and gastrointestinal stromal tumor of the stomach: a case report with immunohistochemical and molecular genetic analyses of KIT and PDGFRA 
Although the stomach is the most common location for gastrointestinal stromal tumor (GIST) with co-primary tumors, the synchronous appearance of a poorly differentiated neuroendocrine carcinoma (NEC) and GIST in the stomach is extremely rare. To the best of our knowledge, this is the first case of gastric GIST coexisting with gastric NEC to be reported in the literature. The current study reports the case of a 71-year-old male with gastric poorly differentiated NEC and GIST discovered incidentally during surgical treatment of the NEC. Immunohistochemistry analysis showed that the NEC tumor cells were positive for CK (cytokeratin), CD57, synaptophysin, chromogranin, CD117 (KIT protein), Dog-1 (discovered on GIST-1 protein) and CD34. The synchronous GIST immunophenotype showed positivity for CD117, Dog-1 and CD34 (100%), whereas staining for CK, SMA, desmin and S100 was negative. Ki-67 labeling of proliferating cells was 90% in NEC and 1% in GIST. An accurate diagnosis was confirmed by immunohistochemical findings. Furthermore, genetic analysis using PCR direct sequencing identified no mutations in the KIT (exons 9, 11, 13 and 17) and PDGFRA (exons 12 and 18) genes. The patient developed lymph node metastases and underwent cisplatin-based chemotherapy after the operation. This is the first documented case of synchronous gastric GIST and NEC with the examination of protein expression and gene mutations in KIT and PDGFRA, which will help to further understand the etiology and pathogenesis of NEC coexisting with GIST in a gastric location.
PMCID: PMC4313951  PMID: 25674291
Snchronous tumor; neuroendocrine; carcinoma; GIST; gastric
24.  Design of activated serine-containing catalytic triads with atomic level accuracy 
Nature chemical biology  2014;10(5):386-391.
A challenge in the computational design of enzymes is that multiple properties must be simultaneously optimized -- substrate-binding, transition state stabilization, and product release -- and this has limited the absolute activity of successful designs. Here, we focus on a single critical property of many enzymes: the nucleophilicity of an active site residue that initiates catalysis. We design proteins with idealized serine-containing catalytic triads, and assess their nucleophilicity directly in native biological systems using activity-based organophosphate probes. Crystal structures of the most successful designs show unprecedented agreement with computational models, including extensive hydrogen bonding networks between the catalytic triad (or quartet) residues, and mutagenesis experiments demonstrate that these networks are critical for serine activation and organophosphate-reactivity. Following optimization by yeast-display, the designs react with organophosphate probes at rates comparable to natural serine hydrolases. Co-crystal structures with diisopropyl fluorophosphate bound to the serine nucleophile suggest the designs could provide the basis for a new class of organophosphate captures agents.
doi:10.1038/nchembio.1498
PMCID: PMC4048123  PMID: 24705591
25.  Prospective evaluation of serum sarcosine and risk of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial 
Carcinogenesis  2013;34(10):2281-2285.
Metabolomic profiling has identified, sarcosine, a derivative of the amino acid glycine, as an important metabolite involved in the etiology or natural history of prostate cancer. We examined the association between serum sarcosine levels and risk of prostate cancer in 1122 cases (813 non-aggressive and 309 aggressive) and 1112 controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Sarcosine was quantified using high-throughput liquid chromatography–mass spectrometry. A significantly increased risk of prostate cancer was observed with increasing levels of sarcosine (odds ratio [OR] for the highest quartile of exposure [Q4] versus the lowest quartile [Q1] = 1.30, 95% confidence interval [CI]: 1.02, 1.65; P-trend 0.03). When stratified by disease aggressiveness, we observed a stronger association for non-aggressive cases (OR for Q4 versus Q1 = 1.44, 95% CI: 1.11, 1.88; P-trend 0.006) but no association for aggressive prostate cancer (OR for Q4 versus Q1 = 1.03, 95% CI: 0.73, 1.47; P-trend 0.89). Although not statistically significant, temporal analyses showed a stronger association between sarcosine and prostate cancer for serum collected closer to diagnosis, suggesting that sarcosine may be an early biomarker of disease. Interestingly, the association between sarcosine and prostate cancer risk was stronger among men with diabetes (OR = 2.66, 95% CI: 1.04, 6.84) compared with those without reported diabetes (OR = 1.23, 95% CI: 0.95–1.59, P-interaction = 0.01). This study found that elevated levels of serum sarcosine are associated with an increased prostate cancer risk and evidence to suggest that sarcosine may be an early biomarker for this disease.
doi:10.1093/carcin/bgt176
PMCID: PMC3786375  PMID: 23698636

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