方法学培训ppt 1、临床研究选题

1、临床研究选题彭晓霞（） 临床流行病学与循证医学中心 首都医科附属北京儿童医院国家儿童医学中心 2018.8.24 三人行必有我师焉3,030,000条记录 可以提出什么问题？ 参考区间是什么？ 儿童血小板计数的参考区间是多少？ 参考区间准确吗？ 男孩和女孩的参考区间一样吗？ 有没有年龄差别？ 高于上限值多少可能是病理改变？ 参考区间（Reference Interval, RI） 同质“健康个体”某一生理指标测量值的95%分布区间 统计学概念 区分“正常”与“异常” 不是诊断标准 不是医学决定值 Ref. Kotz M. Encyclopedia of

2、 Statistical Sciences. New York: Wiley, 2006: 53943.美国目前采用的儿童血常规参考区间 田 Sup p lem ental Tab le 3 Pediatric reference intervals 丘 om clinical laboratory in UCSF(University of California, San Francisco)*.,灶玄儿奇也 f究 NS HOSPITALRBC countage,*1012心 H GB心 g/如 HCT心 1/WBC Count+* 109心 Platelet count心 *109心 0-

3、7 days心 4.0-6.6心 14.5-22.5心 45-67心 0-24 hours:+J1 40-450心9.0-38.0+8-14 days+3.9-6.3心 13.5-21.5心 42-66心 24 hours-7 days:+5.0-34.0+2-4 weeks心 3.6-6.2心 12.5-20.5 心 39-63心 1 week-6 months：心 5.0-21.0+1 -2 mont hs心 3.0-5,4,10.0- 18.0心 31-55心 千 2-3 mont hs心 2.7-49心 9.0-14.0心 28-42心 千 3-6 mont hs心 3.1-45心 9

4、.5-13.5心 29-41心 千 6-24 months+3.7-47心 11.0-13.5心 33-39心 6 mont hs-4 years:+5.5-17.5+2-6 ye缸 S心 3.9-49心 2-5 years: 11.2-13.5心 2-5 years: 34-40心 4-14 years:4.5-15.5+6-12 years心 4.0-5.0心 5-8 years: 11.4-15.5心 5-12 years: 35-45心 千 6-12 years4 .0-5.08-12 years: 11.6-15.5 心 心 十 Male 12-18 years心 4.2-5.6心

5、Male 12-15 years:Male 12-15 years:1 4 -21 years: 4.5-13.2心 12.3-16.0心 37-49心 Male 12-18 years4 .2-5.6Male15-18years:Male 15-18 years:18 yea.rs心 4.4-5.9心 13.6 -17.5心 41-53心 21 ye釭 s: 3.4-10.0+Female12 years心 4.0-5.2 心 Fema le 12-15 years:36-46心 千 11.8-15.5心 Fema le 15-18 years:心 心 12.0-15.5心 心 心 研心 心

6、 千 心 心 心 心 心 口 *Data from htt12://labmanua l/画 tl坚rntzn/test/refra坚 e.html(Accessed 17 .01.08 ).-How about pediatric RIs in China?RI for Children aged 1 toRI for Children aged 1 18 years recommend into18yearsusedinZhu Futang Practice ofBeijingChildrens PediatricsHospitalRIforadults（ W

7、S/T405- 2012）RBC（1012/L） 4.0-4.53.5-5.5Male4.3-5.8Female3.8-5.1Hb（g/L） 120-140110-160Male130-175Female115-150Hct（%） 0.37-0.500.35-0.55Male0.40-0.50Female0.35-0.45WBC（109/L） 8-104-103.5-9.5Plt（109/L） 100-300100-400125-350SourceZhu Futang Practice of Pediatrics (8th edition). Beijing: Peoples Medical

8、Publishing House. 2015.National Guide to Clinical Laboratory Procedures (Forth Edition)研究问题：中国现有儿童参考区间是否适用？Conte nts lists availa ble at S cie nce Di rec tClinica Chin1ica Actajo u r na l homepage: w w w . e ls e v ie r . c o m /l o c at e / c l in chi mnt,ClrinaCrossMarTICLEINFOABSTRACTe histo吓 i础

9、8即 uary2m7i咄 inrevised form 13March 2017peed 14 March 2017lable on line 16 Ma r中 2017,ords. 3 ricsp屈 e blood count ofran驴 Background: We examined the critical gap for pediatric reference intervals in China byvalidating 3 existing pedi- atric reference intervals (Rls of complete blood count(CBC) resp

10、ectively.Meth ods: A tota l of 2255 hea lt hy children attended physica l examination in Beijing Childrens Hospital. Fastedbloodwassampledand CBC.inclu:lingredbloodcell(RBC) count. hemoglobin(HGB). hematocrit(HCT).platelet count ( PLT) andwhite blocxl cell (WBC) count were measured by automated hema

11、tological analyzer Sysmex Xs- 800i. The observed proportions of out-of-range (OOR ) values were calculated by three Rls in order toexamine its applicabilify.Resttlcs: Compared with Rls of CBC recommended by Zhu Futang Practice of Pediatrics, the upper side OORs of RBC count, HGB, WBC count, and PLT

12、deviated from upper refe rence limit, which ranged from 10% to 91.9%. On the contrary, the lower side OOR ofWBC count was 拉 Compa咄 with Chinese adult Rls. the upper side OORs of WBC count and PLTwere 10%. While the lower sides OORs ofRBC count, HGB and HCTwere 10 % among b咑 s 14 y. lt appears that t

13、he Rls validate d by Be iji ng Chil d冗 ns Hospital we芘 relatively accurate Rls for chi! drenCond usions: There is a gap for pediatric Rls in China. It is imperative to initiate research on establishing and val- ,. idaling pediatric Rls in China.To figure the gap among existing RIs Participants A tot

14、al of 2 255 healthy children Volunteered for physical examination at Beijing Childrens Hospital In the summer holiday of 2015 The study was approved by the Ethics Committee of Beijing Childrens Hospital Affiliated to Capital Medical University, Beijing, ChinaAgeBoys n(%)Girls n(%)Total n(%)153（4.4%）

15、 57（5.6%） 110 (4.9%)292（7.6%） 67（6.5%） 159 (7.1%)3102（8.4%） 88（8.6%） 190 (8.5%)491（7.5%） 65（6.3%） 156 (7.0%)5101（8.3%） 83（8.1%） 184 (8.2%)6102（8.4%） 87（8.5%） 189 (8.4%)790（7.4%） 75（7.3%） 165 (7.4%)873（6.0%） 56（5.5%） 129 (5.8%)975（6.2%） 69（6.7%） 144 (6.4%)1060（4.9%） 68（6.6%） 128 (5.7%)1158（4.8%） 57（5

16、.6%） 115 (5.1%)1270（5.8%） 57（5.6%） 127 (5.7%)1357（4.7%） 46（4.5%） 103 (4.6%)1460（4.9%） 46（4.5%） 106 (4.7%)1535（2.9%） 39（3.8%） 74 (3.3%)1648（4.0%） 30（2.9%） 78 (3.5%)1727（2.2%） 19（1.9%） 46 (2.1%)1820（1.6%） 16（1.6%） 36 (1.6%)Total1214(54.2%)1025(45.8%)2239（100.0%）The characteristics of participants (n=2

17、239)The distribution of CBC indexes by gendernMeanSDMinimumMaximumRBCBoys12144.780.393.476.37(*1012/L)Girls10254.600.353.425.94HGBBoys1214138.2413.6491.00185.00(G/dL)Girls1025133.8610.1994.00166.00HCTBoys121439.893.7329.1053.30(%)Girls102538.842.7828.3047.30WBCBoys12147.601.803.8015.10(*109/L)Girls1

18、0257.531.833.4015.30PLTBoys1214288.8064.1096.00526.00(*109/L)Girls1025289.2262.24101.00498.00The distribution of RBC by age and gender6.56.05.5genderboys girls5.04.54.03.53.012345678910 11 12 13 14 15 16 17 18ageThe distribution of HGB by age and gender200180gender boysgirls1601401201008012345678910

19、 11 12 13 14 15 16 17 18ageThe distribution of WBC by age and gender161412genderboys girls10864212345678910 11 12 13 14 15 16 17 18ageStandard normal deviate test for subgroup partitioningValidation of various sources pediatric RIs儿童不同于成人 成人血清肌酐参考范围 （umol/L） 男（20-59岁）：57-97 女（20-59岁）：41-73 男（60-79岁）

20、：57-111 女（60-79岁）：41-81 Ref. 全国临床检验操作规程（第4版） 图1 儿童血肌酐检测值分布 中国儿童常规检验指标参考区间建立与验证项目组织单位：国家卫生计生委医政医管局 项目牵头单位：国家儿童医学中心 首都医科附属北京儿童医院技术支撑单位： 医学会检验分会、国家卫计委临床检验中心 项目 负 责人：倪鑫 起 止 年 限：2016年1月至2018年12月 DE GRUIYTERClim Chem 匡 b Med 2018;. x.(x): x.xx双 XXiaoxia Penga, Yaqi Lv Gu oshuang Feng, Yaguang Peng, Qi li

21、ang Li, Wenqi Song* and Xi n Ni*Algorithm on age partitioningfor estimationAL of refe,re,nce, i nt e,r val s using clinical laboratory database, exemplif,iedwith plasma cr eat i nin, elhttps:/do /10.1515/ cclm-2017-1095!Received INovembe 24 , 2017; accepted Janu ary 31, 2018 AbstractBa ckg loun

22、d: We describe an algorithm to determine age part:iJt:iJon ed refer,ence intenrals (Ris) exemplified fo,r ere atmine using data collection from thed irucal laboratory database.Methods: The data were acqu让e d from the tes t results of creatin.ine of t 64,710 outpatients aged 18 years in Beijing Child

23、rens Hos pital labo rato,ries databases between January 201!6 and De; ember 2016. The tendency of se rum creatinine with age was examin ed 啦 ually using box plot by gende r first. The age subgroup was divided automa ti 三cally by the decision tree method. Subsequently, the sta tistical tests of the d

24、ifference between subgroups were performed by Harris三 Boyd and Lahti methods.Re s u Its: A to tal of 1!36,546 s ampnes after data d eaning were analyzed to explo,re the partition of age group forserum creatinine from birth to 17 years old. Ihe s噶 gested a:ge partitioning of 团 s for creatinine hy the

25、 decision tree m.ethod were for eight subgroups. The difference between a:ge subgroups was demonst rated to bes扫tistically sig血icant by Harris -Boyd and Lahti methods. In addition, the results of age pa:rtitioni:ng for Rls estimation were similar to the suggested age parti廿oning by the Canadian Labo

26、三ratory Initiative in Pediatric Reference Intervals study.Las tly, a suggested algo was developed to proviide potential methodological considerations on age partition mg for Ris es timation .Concl11s io ns: 却 p ropriate age pa:rtitioni:ng 芷 ve ry impo,r三tant for estab lishin g more accura te IRis. T

27、he procedu re to ex:p,lore the age partitioning using d in:itca laborato ry data was developed and evaluated m this study, and 面 l1 pro vide more op inions for designing research on estahl 达 h ment ofRs.Ke ywords: age partitioning; clinical laborato 对 database ; pediatrk; reference mtervals.Comparis

28、on with serum creatinine data from CALIPER studyRef. Clin Chem. 2012;58(5):854-868.Splitting procedure by decision tree techniqueTable 3: Statii sti cal tests for age partition ii ngof Rl s estimation by LahUsmethod,.花 !OSPITALCompaison6mupBoth gendeSFemaleMale numbeOOR斗OOR-Result0OOR-OOR- ResultOOR

29、-OOR-Resultlower,%upper, %lower, %uppe几， l owe,% upper,%1O to3 days0.9346. 86寸3 days to 1 yea 2. 5,60.4323 days to 1yea 6.361. 75寸1 to 4, years0.672,. 7931 to -4 years3.80O. 28v4 to 7, years0.565. 5644 to 7 years3.650.45v7 to 10yea S0.884. 9757 to 10years3.160.81v10 to 13 years1.394.78610to 13 years

30、3.000.69v3.061.08v2.940,. 49寸1 3to 15 years1.176.981.065.791.237.47713 to15 years3.071.24寸 3.241.50v3.200.85v15 to 18 yea乃 1.064.930.964.410.965.97ooR (out ofang:e) was cal.cullated as proportions of subgroups distribution outside reforence llimits estab llished by combiinedl neiighboring subgroups.

31、 bl f p,artitioning was ano,w,ed,esults would be ma k.ed by V; lllf pa titioning was not allowed, results would be ma ked by “ X ”灶玄儿奇也 f究 BEIJING CHILDRENS HOSPITALTable4: Age艺 and gen de 琶specific group fo seum creatii nin,e f om three souc,es.A驴 range (2012 Enzymatic) 4Ager:an驴 (2012Jlaffe)41A驴 r

32、ange(2017 BCH Enzymat ica)SubgrouppariitionMean, Jl!mol/LSubgro11p partiUonMean 湛 mol/LSubgoup pa ii tion, Mean,imol/lo to 14 ,days M+F55.31o to 14 days M+F,61.56o to 2 days M+F50.3415 dlays to2years M+F20.2615 daysto1year M+F38.023 days to 1, year M+F21.692 to5years M+F27.071 to 4 years M+F41.041 t

33、o - 4 years M+F26.2:65 to 11years.M +IF40.84- 4 to 7 years M+F46.864 to 7 years M+F32.96nto15 yearsM+F53.227 to 12years M+F53.207 to 10 years M +F39.0815 to19 yeas lf58.6612 to 15 years M +If,60.3610to 13 yeasM +lf43.9815 to 19 years M74.5415 to 17 years F,63.5913 to 15 years f48.1315 to 17 years M7

34、3.1413 to 15 years M53.4617 to 19 years F,63.0815 to 18 years F52.2617 to 19 years M77, 3115to Visual examination of the frequency distribution -Not partitioning M an uscri pt s with DecisionsACTIONS仅 ru sIDT1TlESUBMIT 花 D DECI SIO NED, Accept (31-Jan-CCLM2 017.1095.R4 Algoithm on age30-Jan-2 018 31

35、-Jan-2018 2018)partitioning for estimationofeference intervals, Productionu sing clinical laboratoryProcessingdatabaseexempli fied with plasma creatinine/1ew Submissionview decision lenera revision has been Revise with MinorCCLM2 017.1095.R3 Algor1thm on age26-Jan- 2018 29-Jan-2018 sutmittedModi ca

36、tions (29-partitioning for estimationStatistical significant for subclasses?at partitioningAdjudicatingby clinicianCombining subclassesCut-off point for age(CCLM2 017.1095.R4)Jan-2018)of reference intervalsusing clinical laboratory aevision hasdatabaseexemplified withbeen submittedplasma creatinine

37、View Submissiona revision has beenview decision letter Revise with MinorCCLM 2017_1095_R2 Algorithm on age21-Jan-2 018 24-Jan-2018sutmittedModifications (24-pa rtitioning forestimation(CCLM2 017.1095.R3)Jan-2018)of reference intervals using clinical laboratory aevisionhasdatabaseexemplified withbeen

38、 submittedplasma creatinine View SubmissionDetermination of age partitionPRINCE研究的数据 灶古 ）l尨务 足 冷 5 0 04 5 0O。_ O。 。5句oO。 。000。衾0佥0。1 015-ALOI* ) 忑 諒l e s土0 _0 2 5 - 0 _9I 姿言。年龄（年） 孕妇？新生儿？临床研究问题创新？应用？如何创新？ Reading after a certain age, diverts the mind too much from its creative pursuits. Any man who

39、reads too much and uses his own brain too little falls into lazy habits of thinking.学而不思则罔思而不学则殆 一个故事一系列问题 青光眼的主要症状是什么？ 一个故事一系列问题 是不是所有的青光眼患者都有眼压高？ 一个故事一系列问题 如果眼压不高，视神经损伤是如何发生的？ 一个故事一系列问题 颅内压和视神经蛛网膜间隙压力之间的关系？ 一个故事一系列问题 能改变临床实践吗？ 提高临床实践能力与质量 有经验要分享 有问题要解决 为什么 做研究？ 为什么写论文？ 一篇文献引出的新问题 Lo-Coco F, Avvisa

40、ti G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-21. 您有什么反应？ 主鸿鹄简介 北京 血液病研究所主任医师， 国际AP屯 金会专家委员会委员 近5年第一通讯作者SCI论文 24 篇 ，影响因子325 分， 新英棺兰医学杂志 2篇、 柳叶刀肿瘤 1 篇、 丿co 1 篇 Blood3篇 Leukem ia 1 篇 主持科技部重大专项1项 国自然2项 临床研究成果影响3个国际指南和3个国内指南 关于靶向药

41、，NEJM与LANCET的习惯是什么？The N E W 匕 N GLAND JOU RN AL of M E D l C il. 卢 灶玄儿奇也 f究 Resistance to Arsen ic Therapy in Acute Promyelocytic LeukemiaBEIJING CHILDRENS HOSPITALTO THE EDITOR: Acute promyelo cy t ic leukemia (APL) is a highly curable disease. Recently, two random iz ed t ria ls conducted by Lo -

42、 Coco et al.1 and our group2 provided strong evidence sup porting front-line treatment with arsenic t riox id e a n d a ll- t ra ns re ti no ic a ci d (AT.RA) for APL. This treatment has been adopted by the most recent.a tiona l Comprehensive Cancer N画 o r k g u id elin es .1 The d i re ct-binding t

43、a rge ts of arsenic tri oxide inthepromyelo cy tic leu kemia protein (PML) B2 domain are required to induce a molec ular response in APL.34 M u ta n t PM L-C21 2/21 3 h a s been shown to lead to resistance to a rsenic trioxide in a.n ex v ivo m od el, but this associa tio n has not been observed in

44、patients with APL.4 Thus far, ony muta tio ns in PML re sulting in the am ino acid substitu tio ns of A216V and L218P have been detected in 彻 o pa tie nts w ith APL thatwas resistant to arsenic t rio x ide.5 Theeffect ofFigure l (facing page). Promy e llocytic Le ulke m ia Protein (PML)-Retinoic Aci

45、d Rec e ptor Al pha (RARA) Mu tat ions in Patie nts wit h Re lapsed Acute Promyelocytic Le u ke m ia (A PL), Longitudinal An alysis I nvolving 4 Patie nts with Muta tio ns, and the Outco mes of 3S Patie ntswith Re llapsed APL in th is Study.I n Pane l A , d ata at the to p sh ow the PML a nd RARA mu

46、 tati ons tha t were repor ted i n othe r s tud i es,35 a nd those at the bo tt om were de te cte d i n the 35 pa tients in ou r s tudy with re l a ps ed AP L. The m u tat ions i n re d were re po rted in ou r study, a nd the nu m be rs in pa re nt he se s i nd icate the n u mb er of pa ti ents harb

47、o ri n g th e mut at ion. lln Pane l B, da ta on 4 pat ient s i n whom l ongitud ina lst u d ies were tec h n ical ly fea s i ble are sh own . The pe r centages nea r the as te ris ks represent th e relative pe r centage of the mutated genes as compa re d w i th the non mut at ed genes雪 AT RA de no

48、tes all-trans re ti n oic a cid,CR com ple te re mi ssion, HSCT hemato poietic s tem-c e l l t ra n spla n tat ion, a nd NR no remission. In Pa n el C, the o ut com es of 35 pati ent s with re la psed A Pl accord i n g to the presenc e or absence o f a rsen ic resi stance and PML m u ta tion s tat us are sh own .PML m u ta tio n s on re s is ta n ce to a rs en ic a n d t h e 35 Pat ie nts had re lla pse13 H ad a rse nic-res iis tant d i sease22 Did not have arse nic-res ist ant d ise ase灶玄儿奇 也f究 BEIJING CHILDREN