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Shared genetic architecture highlights the bidirectional association between major depressive disorder and fracture risk

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General Psychiatry 2024年第3期37卷 352-363页

作者： Pianpian Zhao Zhimin Ying Chengda Yuan Haisheng Zhang Ao Dong Jianguo Tao Xiangjiao Yi Mengyuan Yang Wen Jin Weiliang Tian David Karasik Geng Tian Houfeng Zheng The Affiliated Hangzhou First People’s Hospital School of MedicineWestlake UniversityHangzhouZhejiangChina Westlake Laboratory of Life Sciences and Biomedicine HangzhouZhejiangChina Diseases&Population(DaP)Geninfo Lab School of Life SciencesWestlake UniversityHangzhouZhejiangChina Institute of Basic Medical Sciences Westlake Institute for Advanced StudyHangzhouZhejiangChina Department of Orthopedic Surgery The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina Department of Dermatology Hangzhou Hospital of Traditional Chinese MedicineHangzhouZhejiangChina Department of Global Statistics Eli Lilly and CompanyBranchburgNew JerseyUSA Azrieli Faculty of Medicine Bar-Ilan UniversitySafedIsrael Binzhou Medical University YantaiShandongChina

Background There is limited evidence suggesting that osteoporosis might exacerbate depressive symptoms,while more studies demonstrate that depression negatively affects bone density and increases fracture *** To explore the relationship between major depressive disorder(MDD)and fracture *** We conducted a nested case-control analysis(32670 patients with fracture and 397017 individuals without fracture)and a matched cohort analysis(16496 patients with MDD and 435492 individuals without MDD)in the same prospective UK Biobank data ***,we investigated the shared genetic architecture between MDD and fracture with linkage disequilibrium score regression and the MiXeR statistical *** used the conditional/conjunctional false discovery rate approach to identify the specific shared *** calculated the weighted genetic risk score for individuals in the UK Biobank and logistic regression was used to confirm the association observed in the prospective *** We found that MDD was associated with a 14%increase in fracture risk(hazard ratio(HR)1.14,95%CI 1.14 to 1.15,p<0.001)in the nested case-control analysis,while fracture was associated with a 72%increase in MDD risk(HR 1.72,95%CI 1.64 to 1.79,p<0.001)in the matched cohort analysis,suggesting a longitudinal and bidirectional ***,genetic summary data suggested a genetic overlap between MDD and ***,we identified four shared genomic loci,with the top signal(rs7554101)near *** protein encoded by SGIP1 is involved in cannabinoid receptor type 1 *** found that genetically predicted MDD was associated with a higher risk of fracture and vice *** addition,we found that the higher expression level of SGIP1 in the spinal cord and muscle was associated with an increased risk of fracture and *** The genetic pleiotropy between MDD and fracture highlights the bidirectional association observed in the epidemiological *** shared ge

关键词： fracture matched osteoporosis

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Genomic alterations and molecular subtypes of gastric cancers in Asians

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Chinese Journal of Cancer 2016年第8期35卷 403-409页

作者： Xiang S.Ye Chunping Yu Amit Aggarwal Christoph Reinhard lilly(China) R&D Center lilly Research Laboratories Lilly Corporate CenterEli Lilly and Company

Gastric cancer(GC) is a highly heterogenic disease,and it is the second leading cause of cancer death in the *** chemotherapies are not very effective for GC,which often presents as an advanced or metastatic disease at *** options are limited,and the prognosis for advanced GCs is *** landscape of genomic alterations in GCs has recently been characterized by several international cancer genome programs,including studies that focused exclusively on GCs in *** studies identified major recurrent driver mutations and provided new insights into the mutational heterogeneity and genetic profiles of *** analysis of gene expression data by the Asian Cancer Research Group(ACRG) further uncovered four distinct molecular subtypes with well-defined clinical features and their intersections with actionable genetic alterations to which targeted therapeutic agents are either already available or under clinical *** this article,we review the ACRG GC *** also discuss the implications of the genetic and molecular findings from various GC genomic studies with respect to developing more precise diagnoses and treatment approaches for GCs.

关键词： Gastric cancer Cancer genome Molecular subtyping Heterogeneity Oncogenic drivers Targeted therapy

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Analysis of Pathway Activity in Primary Tumors and NCI60 Cell Lines Using Gene Expression Profiling Data

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Genomics, Proteomics & Bioinformatics 2007年第1期5卷 15-24页

作者： Xing-Dong Feng Shu-Guang Huang Jian-Yong Shou Bi-Rong Liao Jonathan M. Yingling Xiang Ye Xi Lin Lawrence M. Gelbert Eric W. Su Jude E. Onyia Shu-Yu Li Integrative Biology Lilly Research Laboratories Eli Lilly and Company Lilly Corporate Center Indianapolis IN 46285 USA Global Discovery ＆ Development Statistics Lilly Research Laboratories Eli Lilly and Company Lilly Corporate Center Indianapolis IN 46285 USA Cancer Discovery Research Lilly Research Laboratories Eli Lilly and Company Lilly Corporate Center Indianapolis IN 46285 USA

To determine cancer pathway activities in nine types of primary tumors and NCI60 cell lines, we applied an in silico approach by examining gene signatures reflective of consequent pathway activation using gene expression data. Supervised learning approaches predicted that the Ras pathway is active in -70% of lung adenocarcinomas but inactive in most squamous cell carcinomas, pulmonary carcinoids, and small cell lung carcinomas. In contrast, the TGF-β, TNF-α, Src, Myc, E2F3, and β-catenin pathways are inactive in lung adenocarcinomas. We predicted an active Ras, Myc, Src, and/or E2F3 pathway in significant percentages of breast cancer, colorectal carcinoma, and gliomas. Our results also suggest that Ras may be the most prevailing oncogenic pathway. Additionally, many NCI60 cell lines exhibited a gene signature indicative of an active Ras, Myc, and/or Src, but not E2F3, β-catenin, TNF-α, or TGF-β pathway. To our knowledge, this is the first comprehensive survey of cancer pathway activities in nine major tumor types and the most widely used NCI60 cell lines. The ＂gene expression pathway signatures＂ we have defined could facilitate the understanding of molecular mechanisms in cancer development and provide guidance to the selection of appropriate cell lines for cancer research and pharmaceutical compound screening.

关键词： cancer pathways gene expression profiling supervised learning classification

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Treatment preferences in men with erectile dysfunction： an open label study in korean men switching from sildenafil citrate to tadalafil

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Asian Journal of Andrology 2007年第6期9卷 760-770页

作者： Tai Young Ahn Sung Won Lee Sae-Woong Kim Dae Yul Yang Nam Cheol Park Kweon-Sik Min Kwangsung Park Jae-Seung Paick Yulia Dyachkova Trisha Dwight Myung-Sea Luke Lee Asan Medical Centre Seoul 138-736 Korea Samsung Medical Centre Seoul 135-710 Korea Youido St Marys Hospital Seoul 150-713 Korea Kang Dong Sacred Heart Hospital Seoul 134-701 Korea Pusan National University Hospital Pusan 602-739 Korea Pusan lnje University Paik Hospital Pusan 614-735 Korea Chonnam National University Hospital Gwangju 501-757 Korea Seoul National University Hospital Seoul 110-744 Korea Area Medical Centre Vienna Eli Lilly Austria Sydney A-1030 Australia Intercontinental Information Sciences Eli Lilly Australia Sydney 2113 Australia eli lilly korea Seoul 135-280 Korea

To evaluate patient preferences for sildenafil citrate or tadalafil （PDE-5 inhibitors available for the treatment of erectile dysfunction [ED]） and assess potential reasons for these preferences. Methods： This open-label study was conducted on korean men taking sildenafil, at least 6 weeks prior to study entry, for ED. Following screening, patients continued sildenafil treatment for 4 weeks, then after a 1-week washout period, switched to tadalafil for 8 weeks. Patients then continued with their treatment of choice during an extension phase. Psychosocial factors （time concern, spontaneity, sexual self-confidence） were evaluated using Psychological and Interpersonal Relation- ship Scales （PAIRS）, while timing of dose to sexual attempt patterns were assessed from patient diaries. Results： The present study enrolled 160 korean men （mean age 55 years） with prior median sildenafil use of 585 days. During the extension phase, 73.7% of patients elected to take tadalafil, whereas 26.3% chose sildenafil （P 〈 0.001）. After switching from sildenafil to tadalafil, mean PAIRS time concern scores decreased from 2.54 to 2.42 （P = 0.002）, with no statistically significant differences observed between the sildenafil and tadalafil assessment phases in sexual spontaneity and self-confidence scores. Sexual attempts made 〉 4 h to 〈 36 h post-dose occurred in 4.5% of patients during the sildenafil assessment phase compared with 17.5% during the tadalafil assessment phase. Conclusion： After experiencing both sildenafil and tadalafil, the majority of patients exhibited a preference for tadalafil. This preference might be influenced by psychosocial factors, such as decreased time concerns, and a broader window of opportunity available for sexual activity.

关键词： erectile dysfunction tadalafil sildenafil citrate Psychological and Interpersonal Relationship Scales preference

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Second-line treatment of advanced hepatocellular carcinoma:Time for more individualized treatment options?

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World Journal of Hepatology 2022年第6期14卷 1074-1086页

作者： Senthil Rajappa Kun-Ming Rau Palanki Satya Dattatreya Anant Ramaswamy Philana Fernandes Aarohan Pruthi Rebecca Cheng Mariusz Lukanowski Yi-Hsiang Huang Department of Medical Oncology Basavatarakam Indo-American Cancer Hospital and Research InstituteHyderabad 500034TelanganaIndia College of Medicine I-Shou UniversityKaohsiung 822Taiwan Department of Oncology Omega HospitalHyderabad 500034India Department of Oncology Tata Memorial HospitalMumbai 400012India Global Scientific Communications Eli Lilly and Company LtdCork 48006CorkIreland Medical Affairs Eli Lilly IndiaHaryana 122001India Medical Affairs Eli Lilly TaiwanTaipei 10543Taiwan Medical Affairs Eli LillyHerlev 2370Denmark Division of Gastroenterology and Hepatology Department of MedicineTaipei Veterans General HospitalInstitute of Clinical MedicineNational Yang-Ming Yang Ming Chiao Tung University School of MedicineTaipei 112Taiwan

Hepatocellular carcinoma(HCC)is the most frequently diagnosed primary tumor of the liver and is usually detected as advanced *** is an aggressive disease that often progresses rapidly when it fails to respond to *** such,patients have limited opportunities to try different subsequent-line treatment *** the last 5 years,the number of agents and/or regimens available for the treatment of advanced HCC has significantly increased,which has made treatment choices for this patient population increasingly *** the secondline setting,several phase III trials of regorafenib(RESORCE),ramucirumab(REACH/REACH-2),and cabozantinib(CELESTIAL)have demonstrated clinically meaningful survival benefits in patients with the ***,the median overall survival of patients with advanced HCC remains unchanged at approximately 12 mo from the start of systemic second-line therapy,with a limited duration of *** from the REACH/REACH-2 trials demonstrated for the first time that baseline alpha-fetoprotein(AFP)levels can be used as an identification factor to select those who are likely to benefit the most from ramucirumab *** is both well tolerated and efficacious and has a clinically acceptable safety ***,it should be considered an option for patients with AFP levels≥400 ng/mL.

关键词： Hepatocellular carcinoma Alpha-fetoprotein Prognostic factor Ramucirumab Second-line treatment Survival

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Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in Chinese postmenopausal women with osteoporosis: a multi-center, randomized, placebo-controlled clinical trial

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Chinese Medical Journal 2004年第7期117卷 1029-1035页

作者：刘建立朱汉民黄琪仁张忠兰李慧林秦跃娟张颖魏道林陆敬辉刘慧陈小平刘玉娟 Abie Ekangaki 郑以漫 Adolfo Diez-Perez Kristine Harper Department of Obstetrics and Gynaecology Department of Gerontology Center for Preventing and Treating Osteoporosis eli lilly and Company

Background Raloxifene has been approved for prevention and treatment of postmenopausal osteoporosis in Caucasian women. It also has some positive effects on serum lipids in Caucasians. The objective of this study was to determine the effect of raloxifene hydrochloride on lumbar spine and total hip bone mineral density (BMD), bone metabolism, and serum lipids in Chinese postmenopausal women with *** This was a multi-center, randomized, double-blind, placebo-controlled clinical trial in which 204 postmenopausal Chinese women with osteoporosis were assigned to receive raloxifene (60 mg) or placebo treatment daily for 12 months. BMD, serum bone metabolism markers, and serum lipids were measured before and after drug administration. BMD was measured by Dual-Energy X-Ray Absorptiometry (DEXA) and bone metabolism markers were analyzed by one-step enzyme-linked immunosorbent assay. Serum lipids were measured by enzymatic *** At the end of the 12-month study, lumbar spine BMD increased in both groups with a mean increase of (3.3±4.8) % in the raloxifene group and (1.0±4.9) % in the placebo group (P0.05). In the raloxifene group, the median decreases in the biochemical markers of bone metabolism serum osteocalcin and C-telopeptide were 41.7% and 61.5%, respectively. These changes were statistically significant compared with those in the placebo group (10.6% and 35.6%, P<0.001, respectively). Both total cholesterol and low-density lipoprotein cholesterol decreased significantly in the raloxifene group compared with those in the placebo group (P<0.001, respectively) and there was no significant effect of raloxifene on high-density lipoprotein cholesterol and triglycerides compared

关键词： raloxifene · bone density · bone metabolism markers · osteoporosis postmenopausal

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Duloxetine versus placebo in the treatment of patients with generalized anxiety disorder in China

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Chinese Medical Journal 2011年第20期124卷 3260-3268页

作者： WU Wen-yuan WANG Gang Susan G Ball Durisala Desaiah ANG Qiu-qing Department of Psychosomatic Medicine Tongji Hospital Tong Ji University Shanghai 200065 China Ninth Ward In-patient Department Beijing Anding Hospital Capital Medical University Beijing 100088 China lilly Research Laboratories Eli Lilly and Company Indianapolis IN 46285-1542 USA eli lilly and Company Shanghai 201203 China

Background Duloxetine is approved for the treatment of generalized anxiety disorder （GAD） in the United States and elsewhere. This study aimed to assess the efficacy, tolerability, and safety of duloxetine in Chinese patients with GAD. Methods This 9-site study consisted of double-blind treatment for 15 weeks either with duloxetine 60-120 mg or with placebo. Patients with at least moderately severe GAD and a Sheehan Disability Scale （SDS） global functioning impairment total score 〉12 were included in this study. Patients who were randomly assigned to duloxetine received 60 mg for 7 weeks; at that point, for nonresponders the dose was increased to 120 mg for the remaining 8 weeks. The primary efficacy measure was mean change from baseline to endpoint on the Hospital Anxiety and Depression Scale-Anxiety subscale score （HADS-A）. Secondary efficacy measures included the Hamilton Anxiety Rating Scale （HAMA）, the SDS, and pain measures. Safety and tolerability were assessed. Results Baseline characteristics did not differ significantly between treatment groups. Mean age of the subjects （n=210） was 37.6 years, 50.5% were female, and 74.3% completed the 15 weeks treatment. Patients treated with duloxetine had significantly greater improvement compared to placebo on the HADS-A （mean change -6.6 vs. -4.9, respectively, P=0.022）. Improvement in anxiety was greater with duloxetine treatment at 7 weeks and continued through 15 weeks for both the HADS-A and the HAMA total score （0.01 〈 P 〈0.05）. Compared with placebo, duloxetine was also associated with greater improvement on most seconda~ measures, but not on the SDS global functioning score. Nausea, dizziness, and somnolence occurred significantly more frequently as treatment-emergent adverse events with duloxetine treatment compared with placebo treatment. Conclusions Duloxetine 60-120 mg once daily is effective and well-tolerated for the treatment of patients with GAD in China.

关键词： generalized anxiety disorder Chinese, patients duloxetine acute, therapy

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Log-rank and stratified log-rank tests

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Statistical Theory and Related Fields 2023年第4期7卷 309-317页

作者： Ting Ye Jun Shao Yanyao Yi Department of Biostatistics University of WashingtonSeattleWAUSA School of Statistics East China Normal UniversityShanghaiPeople’s Republic of China Department of Statistics University of WisconsinMadisonWIUSA Global Statistical Sciences Eli Lilly and CompanyIndianapolisINUSA

In randomized clinical trials with right-censored time-to-event outcomes,the popular log-rank test without adjusting for baseline covariates is asymptotically valid for treatment effect under simple randomization of treatments but is too conservative under covariate-adaptive *** stratified log-rank test,which adjusts baseline covariates in the test procedure by stratification,is asymptotically valid regardless of what treatment randomization is *** the literature,however,under simple randomization there is no affirmative conclusion about whether the stratified log-rank test is asymptotically more powerful than the unstratified log-rank *** this article we show when the stratified and unstratified log-rank tests aim for the same null hypothesis and that,under simple randomization,the stratified log-rank test is asymp-totically more powerful than the unstratified log-rank test in the region of alternative hypothesis that is specified by a Cox proportional hazards *** also provide some discussion about why we do not have an affirmative conclusion in general.

关键词： Baseline covariates covariate-adaptive randomization null hypothesis of no treatment eﬀect Pitman’s relative effciency time-to-event validity of tests

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Menopausal depression:comparison of hormone replacement therapy and hormone replacement therapy plus fluoxetine

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Chinese Medical Journal 2004年第2期17卷 189-194页

作者：刘平何方方白文佩郁琦史蔚吴宜勇贺丹军肖计划郑晔廖秦平 lilly Research Laboratories Eli Lilly Shanghai Representative. Office Shanghai 200001 China Peking Union Medical College Hospital Beijing 100730 China The First Affiliate Hospital Peking University Beijing 100034 China lilly Research Laboratories Eli Lilly Shanghai Representative. Office. Shanghai 200001 China Beijing Hospital Beijing 100730 China People' s Hospital of Jiangsu Province Nanjing 210029 China Huaqiao Hospital Jinan University Guangzhou 510630

BACKGROUND: To compare the efficacy and safety of hormone replacement therapy (HRT) combined with fluoxetine, with HRT alone, in post-menopausal women suffering from depression. METHODS: A randomized, open-label, parallel trial was applied. HRT was administered to all patients for 2 cycles, with 14 days of estrogen therapy and 14 days of estrogen plus progesterone. Patients who were randomly assigned to the HRT plus fluoxetine group were given fluoxetine in combination with HRT. Hamilton Depression Rating Scale (HAMD), Kupperman Menopausal Index (KMI), and Clinical Global Impressions scale were used to measure the efficacy. RESULTS: One hundred and twenty-three post-menopausal patients with depression were enrolled in the study. Among them, 120 had at least one post-treatment visit and entered into the statistical analysis. The mean total HAMD scores were significantly lower, and the percentages of HAMD score reductions were higher in the HRT plus fluoxetine Group compared with the HRT Group, after at least 3 weeks of treatment, with an average difference of 5 points at the endpoint. The Clinical Global Impression-Severity and Clinical Global Impression-Improvement scores were significantly different in the 2 groups, in favor of the combination therapy. The mean total KMI was significantly lower in the Combination Group compared with the HRT Group, after at least 6 weeks of treatment, with an average 4.5-point difference between the groups. No statistically significant differences were found in most of the adverse events reported in the Combination Group compared with the HRT group, with the exception of 3 symptoms, i.e., dry mouth, loss of appetite, and abdominal distention. They were mild to moderate in severity. Two patients in the HRT group, but none in the combination group, dropped out due to adverse events. CONCLUSION: HRT plus fluoxetine therapy was effective in the treatment of menopausal depression with a satisfactory safety profile.

关键词： Estrogen Replacement Therapy Menopause Adult Comparative Study Depressive Disorder Female Fluoxetine Humans Middle Aged Research Support, Non-U.S. Gov't Treatment Outcome

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Improve Survival Prediction Using Principal Components of Gene Expression Data

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Genomics, Proteomics & Bioinformatics 2006年第2期4卷 110-119页

作者： Yi-Jing Shen Shu-Guang Huang Department of Statistics University of California Los Angeles CA 90095-1554 USA Statistics and Information Science Lilly Corporate Center Eli Lilly and Company Indianapolis IN 46285 USA.

The purpose of many microarray studies is to find the association between gene expression and sample characteristics such as treatment type or sample phenotype. There has been a surge of efforts developing different methods for delineating the association. Aside from the high dimensionality of microarray data, one well recognized challenge is the fact that genes could be complicatedly inter-related, thus making many statistical methods inappropriate to use directly on the expression data. Multivariate methods such as principal component analysis （PCA） and clustering are often used as a part of the effort to capture the gene correlation, and the derived components or clusters are used to describe the association between gene expression and sample phenotype. We propose a method for patient population dichotomization using maximally selected test statistics in combination with the PCA method, which shows favorable results. The proposed method is compared with a currently well-recognized method.

关键词： microarray principal component analysis survival

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