1、Clinical Study Design, Analysis, and PresentationYiqing Song, MD, ScDHarvard Medical School Boston, MA, USAJuly, 2009臨床研究設計分析和文章寫作宋一青Study Design (科研設計)Why （為什么要做科研？）臨床體會，經驗是否正確；興趣；等等。What （做什么?）內容包括完整提出自己的假說，新理論、新方法或新模型？或者只是來驗證別人的How （怎么做？)方法的科學性和嚴格性OverviewClinical Study (definition): (定義）Clinical

2、 Study Purpose (臨床研究主要目的）Etiology (病因學） Prediction （疾病預測）Treatment （疾病治療）Study Direction （側重方向） Genetics （基因研究）Biomarkers （生物標記物）Nutrition （營養(yǎng)）Pharmacological agents or surgery （藥物或外科手術）Psychosocial factors （社會心理學） (等等）Key issues in study Design (研究設計的關鍵）Knowledgement in your field （本學科知識）Literature

3、 search （文獻追蹤）Fundamental Study Design(基本研究設計類型）Observational Study (觀察性臨床研究）Ecological Studies (生態(tài)性研究） Case report （病例報告）Cross-sectional Study （橫斷面研究）Case-Control Study （病例對照研究）Prospective Cohort Study (前瞻性定群研究）Retrospective Cohort Study (回顧性定群研究）Intervention Trial （臨床干預試驗） Open Trial （開放性研究）Random

4、ized Trial （隨機干預試驗）Randomized double-blind Trial （隨機雙盲干預試驗）Randomized single-blind Trial （隨機單盲干預試驗）Evidence-based Study （循證醫(yī)學研究） Systemic Review （系統(tǒng)性文獻綜述）Meta-analysis (薈萃分析）大氣污染與糖尿病發(fā)生率的關系出生體重與成人II型糖尿病的關系糖尿病人合并HIV感染的特征分析Examples (實例分析）Case report or case-control studyEcological studyCohort study or

5、Case-control study空腹血糖水平與發(fā)生腫瘤的關系Cohort study；case-control study胰島素治療對糖尿病合并癥的效果Randomized trial； cohort study？新降糖藥的療效Randomized trial基因多態(tài)性與糖尿病的關系Case-control study; cohort study; cross-sectional study新檢測方法對糖尿病預測的改善Cohort study血中幾種檢測標記物的相關性Cross-sectional studySummary （總結） Study Population （研究人群的建立最為關

6、鍵）Representative （代表性） Sample Size （數量）Study Design （研究設計類型）Prospective （前瞻性最優(yōu)，其次，病例對照或橫斷面）Longitudinal （續(xù)貫性）Data Collection (數據收集齊備）Basic characteristics (demographic, geographic, anthropometric, and lifestyle or psychosocial factors)Biological sample collection (blood, toenail, hair, and urine). A

7、ccurate outcome ascertainment (疾病診斷準確）Study Group （研究團隊）Different Research Areas（不同側重點）Multidisciplinary collaboration （多學科協作）Keep track of the latest information (跟蹤最新文獻）臨床資料充分人群特殊橫斷面研究但是人群代表性傳統(tǒng)方法陽性結果臨床資料充分人群特殊同一人群傳統(tǒng)方法陽性結果Common variants in KCNQ1 are associated with type 2 diabetes and impaired fas

8、ting glucose in a Chinese Han population. Hum Mol Genet. 2009Plasma 25-hydroxyvitamin D concentration and metabolic syndrome among middle-aged and elderly Chinese individuals. Diabetes Care. 2009 Jul;32(7):1278-83. RBP4 variants are significantly associated with plasma RBP4 levels and hypertriglycer

9、idemia risk in Chinese Hans. J Lipid Res. 2009 Jul;50(7):1479-86.Association of GCKR rs780094, alone or in combination with GCK rs1799884, with type 2 diabetes and related traits in a Han Chinese population. Diabetologia. 2009 May;52(5):834-43. Associations of inflammatory factors with glycaemic sta

10、tus among middle-aged and older Chinese people. Clin Endocrinol (Oxf). 2009 Jun;70(6):854-62. Epub 2008 Sep 2.Associations of resistin with inflammatory and fibrinolytic markers, insulin resistance, and metabolic syndrome in middle-aged and older Chinese. Eur J Endocrinol. 2008 Nov;159(5):585-93. Co

11、mmon variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population. Diabetes. 2008 Oct;57(10):2834-42. Variants in the fat mass- and obesity-associated (FTO) gene are not associated with obesity in a Ch

12、inese Han population. Diabetes. 2008 Jan;57(1):264-8.Elevated retinol-binding protein 4 levels are associated with metabolic syndrome in Chinese people. J Clin Endocrinol Metab. 2007 Dec;92(12):4827-34. 小型病例對照研究ALS （肌萎縮性脊髓側索硬化癥 ）合適病例對照研究Times cited （累積引用次數）:Google: 1,906ISI: 1,048 課題新穎；臨床意義大；隨機試驗；結果

13、陽性。優(yōu)勢：小樣本；隨機效果是否達到預期；糖尿病的診斷是否一致不足處：20,000 Men and Women will be Randomized in the VITAL TrialVitamin D (1,600IU) N=10,000Placebo vitamin DN=10,000DHA/EPA (1g/day)N=5,000Fish Oil PlaceboN=5,000Flow diagram illustrating the 22 randomly assigned treatment components of the VITamin D and OmegaA-3 TriaL

14、(VITAL), which will start in January 2010. DHA/EPA (1g/day)N=5,000Fish Oil PlaceboN=5,000The VITamin D and OmegaA-3 TriaL (VITAL)8171 Women Randomized in the WACS Trial (June 1995-January 31, 2005)5442 Randomized in the WAFACS Trial (April 1998-July 31, 2005)Daily take of a combination pill of folic

15、 acid and vitamins B6 and B12(n=2,132 free of diabetes at baseline)Daily intake of a placebo pill(n=2,120 free of diabetes at baseline)245 Incident cases259 Incident casesFigure 1. Flow diagram illustrating diabetes outcomes in the randomly assigned treatment of folic acid and vitamins B6 and B12 of

16、 the Womens Antioxidant and Folic Acid Cardiovascular Study (WAFACS). (Song et al. Diabetes, 2009)Log rank test P=0.44Years of Follow-up Folate/B vitamins Group 2132 2044 1935 1815 1738No. at Risk Placebo Group 2120 2017 1901 1789 1720Figure 2. Cumulative incidence of type 2 diabetes by randomized t

17、reatment assignment (active treatment vs. placebo) in the WAFACS. RR= 0.94 (0.79-1.11)Similar Results after censoring non-compliance(Song et al. Diabetes, 2009)0 0.50 1.00 1.50 2.00Relative Risk for Type 2 DiabetesFigure 3.SubgroupFolic Acid/B Vitamin Active GroupPlacebo GroupP value for Interaction

18、Age45-54 yr 57 (0.13) 80 (0.17)No. of cases (%) 55-64 yr 94 (0.12) 95 (0.13)65 yr 94 (0.10) 84 (0.09)1000kcal/wk 74 (0.09) 80 (0.10) Low, 1000kcal/wk 171 (0.13) 179 (0.13)Physical Activity0.360.850.60Current 29 (0.11) 39 (0.15)Past 106 (0.12) 113 (0.12)Never 110 (0.11) 107 (0.12)Cigarette Smoking 0.

19、61Yes 110 (0.15) 140 (0.19)No 123 (0.09) 113 (0.09)Family History of diabetes 0.060.71Tertile 1 (1.82-9.75) 78 (0.11) 75 (0.11)Tertile 2 (9.76-43.7) 81 (0.12) 87 (0.13)Baseline vitamin B12 intake (mcg/d)Tertile 3 (43.8-899) 72 (0.11) 81 (0.12)Tertile 1 (1.82-9.75) 76 (0.11) 77 (0.12)Tertile 2 (9.76-

20、43.7) 83 (0.12) 87 (0.13)Baseline vitaminB6 intake (mg/d)Tertile 3 (43.8-899) 72 (0.11) 79 (0.11)Tertile 1 (1.82-9.75) 78 (0.11) 82 (0.12)Tertile 2 (9.76-43.7) 82 (0.12) 82 (0.12)Baseline folate intake (mg/d)Tertile 3 (43.8-899) 71 (0.11) 79 (0.12)0.900.99SCI-Science Citation Index（科學索引指數）Science Ci

21、tation Index (SCI ) is a citation index originally produced by the Institute for Scientific Information (ISI) in 1960, which is now owned by Thomson Reuters. This database allows a researcher to identify which later articles have cited any particular earlier article, or cited the articles of any par

22、ticular author, or determine which articles have been cited most frequently. Thompson ISI論文檢索數據庫挑選世界上一批有影響的科學刊物，將其論文題目和作者及作者單位、文摘和引用論文進行檢索，建立數據庫，并向世界各地科研單位定期發(fā)行他們的檢索數據庫，為科學工作者提供便捷的論文檢索和引用統(tǒng)計服務。收錄在SCI中的雜志論文比較容易被科研人員檢索查閱。論文絕大多數是英文刊物 （10，000 多種期刊，120，000個國際會議錄）Impact factor（引用因子）The Impact factor was dev

23、ised by Eugene Garfield, the founder of the Institute for Scientific Information (ISI), now part of Thomson, a large worldwide US-based publisher. Impact factors are calculated each year by Thomson Scientific for those journals which it indexes, and the factors and indices are published in Journal C

24、itation Reports. 引用因子是針對某一年的評價指標：舉例來說，2008年的某一個雜志的IF值就是該雜志在2008前兩年（2006和2007）的文章在2008一年內被引用的總次數除以這兩年發(fā)表的文章總數（包括編者按和給編輯的來信）。 Research Results(研究結果）Original Research: 即有原創(chuàng)性的成果。Replication Research: 重復性成果。Comprehensive， Systematic Review （qualitative and quantitative) : 較全面系統(tǒng)的文獻綜述。Manuscript Preparation

25、Originality (Novelty) (內容原創(chuàng)性新穎性) Novel Findings (獨特的發(fā)現)Good writing (可讀性方面) Clear thinking （思路清晰）Logic （邏輯性強）Concise sentence （語句通順）Clear Tables and Figures (表格圖表清晰，信息豐富) 研究論文的大致結構Title （題目）Authors and Affiliation（作者和單位）Abstract （摘要）Introduction （引言）Research Design and Methods (研究設計和方法）Results （結果）D

26、iscussion（討論和結論）Acknowledgement（致謝）References（參考文獻）Tables and Figures (表和圖)Introduction （引言）提出研究動機和目的提出研究問題必須參考引證最新的相關研究文獻Discussion (討論）Summary (概括性總結）Comparison （與其它研究從理論、方法到結果的相同和不同點）Mechanisms （可能的機制討論）Strength and Limitation （本研究優(yōu)缺點）Conclusions （結論和意義）Reference （文獻引用）ENDNOTE （幫助軟件）Keynote paper

27、s （關鍵的文獻）Original paper (原創(chuàng)論文為主）Key review paper (關鍵的綜述性文章）Common Reasons for Paper Rejection（退稿的常見的原因）首先分析向SCI刊物投稿命中率低、退稿率高的原因。研究問題不新穎；2. 實質性內容的原因; -實驗設計缺陷； -數據不全； -分析方法；3. 語言和寫法方面的原因; 4. 無新或重要的補充。僅是簡單重復他人工作。Performance evaluation (業(yè)績評估）Quality （研究質量）Quantity （研究數量）Continuous Contribution （持續(xù)性研究）Researcher potential（研究者潛質）Passionate (熱情）Persistent (堅持）Patient (耐心）An Integrative Paradigm for Medicine and Public Health in the New Millennium（臨床醫(yī)學和公共衛(wèi)生領域在下一世紀的融合發(fā)展）DNARNAProte