The rise of multiple imputation: a review of the reporting and implementation of the method in medical research

BMC Medical Research Methodology

Julie A Simpson²  Katherine J Lee¹  Panteha Hayati Rezvan² 

[1] Department of Paediatrics, The University of Melbourne, Parkville, Melbourne, VIC, Australia;Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Melbourne, VIC, Australia

关键词: Reporting;    Sensitivity analysis;    Multiple imputation;    Missing data;   

Others  :  1177561
DOI  :  10.1186/s12874-015-0022-1

 received in 2014-11-14, accepted in 2015-03-18,  发布年份 2015

【 摘 要 】

Background

Missing data are common in medical research, which can lead to a loss in statistical power and potentially biased results if not handled appropriately. Multiple imputation (MI) is a statistical method, widely adopted in practice, for dealing with missing data. Many academic journals now emphasise the importance of reporting information regarding missing data and proposed guidelines for documenting the application of MI have been published. This review evaluated the reporting of missing data, the application of MI including the details provided regarding the imputation model, and the frequency of sensitivity analyses within the MI framework in medical research articles.

Methods

A systematic review of articles published in the Lancet and New England Journal of Medicine between January 2008 and December 2013 in which MI was implemented was carried out.

Results

We identified 103 papers that used MI, with the number of papers increasing from 11 in 2008 to 26 in 2013. Nearly half of the papers specified the proportion of complete cases or the proportion with missing data by each variable. In the majority of the articles (86%) the imputed variables were specified. Of the 38 papers (37%) that stated the method of imputation, 20 used chained equations, 8 used multivariate normal imputation, and 10 used alternative methods. Very few articles (9%) detailed how they handled non-normally distributed variables during imputation. Thirty-nine papers (38%) stated the variables included in the imputation model. Less than half of the papers (46%) reported the number of imputations, and only two papers compared the distribution of imputed and observed data. Sixty-six papers presented the results from MI as a secondary analysis. Only three articles carried out a sensitivity analysis following MI to assess departures from the missing at random assumption, with details of the sensitivity analyses only provided by one article.

Conclusions

This review outlined deficiencies in the documenting of missing data and the details provided about imputation. Furthermore, only a few articles performed sensitivity analyses following MI even though this is strongly recommended in guidelines. Authors are encouraged to follow the available guidelines and provide information on missing data and the imputation process.

【 授权许可】

   
2015 Hayati Rezvan et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Powney M, Williamson P, Kirkham J, Kolamunnage-Dona R: A review of the handling of missing longitudinal outcome data in clinical trials. Trials 2014, 15(1):1-19.
• [2]Karahalios A, Baglietto L, Carlin JB, English DR, Simpson JA: A review of the reporting and handling of missing data in cohort studies with repeated assessment of exposure measures. BMC Med Res Methodol 2012, 12:96-105.
• [3]Wood AM, White IR, Thompson SG: Are missing outcome data adequately handled? A review of published randomized controlled trials in major medical journals. Clin Trials 2004, 1(4):368-76.
• [4]Schafer JL, Graham JW: Missing data: Our view of the state of the art. Psychol Methods 2002, 7(2):147-77.
• [5]Sterne JAC, White IR, Carlin JB, Spratt M, Royston P, Kenward MG, et al.: Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ 2009, 338:b2393.
• [6]Little RJ, D’Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al.: The Prevention and Treatment of Missing Data in Clinical Trials. N Engl J Med 2012, 367(14):1355-60.
• [7]Ware JH, Harrington D, Hunter DJ, D’Agostino RB: Missing Data. N Engl J Med 2012, 367(14):1353-4.
• [8]National Research Council: Panel on Handling Missing Data in Clinical Trials, Committee on National Statistics, Division of Behavioral and Social Sciences and Education: The prevention and treatment of missing data in clinical trials. National Academies Press, Washington, D.C; 2010.
• [9]Von E, Erik A, Egger DG, Matthias P, Gøtzsche SJ, Vandenbroucke PC, et al.: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. Bull World Health Organ 2007, 85(11):867-72.
• [10]Mackinnon A: The use and reporting of multiple imputation in medical research - a review. J Intern Med 2010, 268(6):586-93.
• [11]Lee KJ, Carlin JB: Recovery of information from multiple imputation: a simulation study. Emerging Themes in Epidemiology 2012, 9(1):3-12.
• [12]R Development Core Team: R: A language and environment for statistical computing, reference index version 2.2.1. Vienna, Austria.ISBN 3-900051-07-0. URL http://www.R-project.org: R Foundation for Statistical Computing; 2005.
• [13]SAS Institute Inc: PROC MI. SAS Procedures Giude, Version 9.2. SAS Institute Inc, Cary, NC; 2008.
• [14]StataCorp: Stata Statistical Software: Release 12. Stata Corp LP, College Station, TX; 2009.
• [15]Little RJA, Rubin DB: Statistical analysis with missing data/Roderick J.A. Little, Donald B. Rubin. Wiley, c2002; 2nd ed, Hoboken, N.J; 2002.
• [16]Rubin DB: Multiple imputation for nonresponse in surveys/Donald B. Rubin. Wiley, c1987, New York; 1987.
• [17]Graham JW: Missing data [electronic resource] : analysis and design/John W. Graham. Springer, c2012, New York, NY; 2012.
• [18]Lee KJ, Simpson JA: Introduction to multiple imputation for dealing with missing data. Respirology 2014, 19(2):162-7.
• [19]Schenker N, Taylor J: Partially parametric techniques for multiple imputation. Comput Stat Data Anal 1996, 22(4):425-46.
• [20]White IR, Royston P, Wood AM: Multiple imputation using chained equations: Issues and guidance for practice. Stat Med 2011, 30(4):377-99.
• [21]Lee KJ, Carlin JB: Multiple imputation for missing data: fully conditional specification versus multivariate normal imputation. Am J Epidemiol 2010, 171(5):624-32.
• [22]Royston P: Multiple imputation of missing values. STATA JOURNAL 2004, 4(3):227-41.
• [23]Van Buuren S: Flexible Imputation of Missing Data: 1st ed. Taylor and Francis, Hoboken; 2012.
• [24]White IR, Carlin JB: Bias and efficiency of multiple imputation compared with complete-case analysis for missing covariate values. Stat Med 2010, 29(28):2920-31.
• [25]Carpenter JR, Kenward MG: Multiple imputation and its application/James R. Carpenter and Michael G. Kenward. 1st edition. Wiley, Chichester; 2013.
• [26]Carpenter JR, Kenward MG, White IR: Sensitivity analysis after multiple imputation under missing at random: a weighting approach. Stat Methods Med Res 2007, 16(3):259-75.
• [27]Ratitch B, O’Kelly M, Tosiello R: Missing data in clinical trials: from clinical assumptions to statistical analysis using pattern mixture models. Pharm Stat 2013, 12(6):337.
• [28]Yuan Y: Sensitivity Analysis in Multiple Imputation for Missing Data. In Proceedings of the SAS Global Forum 2014 Conference:[http://support.sas.com/resources/papers/proceedings14/SAS270-2014.pdf]
• [29]2014 Journal Citation Reports® Science Edition (Thomson Reuters, 2014) [http://thomsonreuters.com/journal-citation-reports]
• [30]Klebanoff MA, Cole SR: Use of multiple imputation in the epidemiologic literature. Am J Epidemiol 2008, 168(4):355-7.
• [31]Burton A, Altman D: Missing covariate data within cancer prognostic studies: a review of current reporting and proposed guidelines. Br J Cancer 2004, 91(1):4-8.
• [32]Abdulla S, Sagara I, Borrmann S, D’Alessandro U, González R, Hamel M, et al.: Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial. Lancet 2008, 372(9652):1819-27.
• [33]Acker MA, Parides MK, Perrault LP, Moskowitz AJ, Gelijns AC, Voisine P, et al.: Mitral-valve repair versus replacement for severe ischemic mitral regurgitation. N Engl J Med 2014, 370(1):23-32.
• [34]Alio AP, Nana PN, Salihu HM: Spousal violence and potentially preventable single and recurrent spontaneous fetal loss in an African setting: cross-sectional study. Lancet 2009, 373(9660):318-24.
• [35]Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al.: Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010, 363(1):24-35.
• [36]Armstrong PW, Gershlick AH, Goldstein P, Wilcox R, Danays T, Lambert Y, et al.: Fibrinolysis or Primary PCI in ST-Segment Elevation Myocardial Infarction. N Engl J Med 2013, 368(15):1379-87.
• [37]Beasley R, Clayton T, Crane J, Von Mutius E, Lai CK, Montefort S, et al.: Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme. Lancet 2008, 372(9643):1039-48.
• [38]Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, et al.: Effectiveness of Sensor-Augmented Insulin-Pump Therapy in Type 1 Diabetes. N Engl J Med 2010, 363(4):311-20.
• [39]Bergenstal RM, Klonoff DC, Garg SK, Bode BW, Meredith M, Slover RH, et al.: Threshold-Based Insulin-Pump Interruption for Reduction of Hypoglycemia. N Engl J Med 2013, 369(3):224-32.
• [40]Boonen S, Reginster J, Kaufman J, Lippuner K, Zanchetta J, Langdahl B, et al.: Fracture Risk and Zoledronic Acid Therapy in Men with Osteoporosis. N Engl J Med 2012, 367(18):1714-23.
• [41]Brott TG, Hobson RW II, Howard G, Roubin GS, Clark WM, Brooks W, et al.: Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010, 363(1):11-23.
• [42]Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D, et al.: Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 2008, 372(9653):1881-93.
• [43]Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al.: Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009, 374(9683):39-47.
• [44]Carlsson LMS, Peltonen M, Ahlin S, Anveden Å, Bouchard C, Carlsson B, et al.: Bariatric Surgery and Prevention of Type 2 Diabetes in Swedish Obese Subjects. N Engl J Med 2012, 367(8):695-704.
• [45]Caroli A, Perico N, Perna A, Antiga L, Brambilla P, Pisani A, et al.: Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial. Lancet 2013, 382(9903):1485-95.
• [46]Chan PS, Nallamothu BK, Krumholz HM, Spertus JA, Li Y, Hammill BG, et al.: Long-Term Outcomes in Elderly Survivors of In-Hospital Cardiac Arrest. N Engl J Med 2013, 368(11):1019-26.
• [47]Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, et al.: Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010, 363(3):233-44.
• [48]Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, et al.: Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet 2012, 379(9823):1301-9.
• [49]Day JN, Chau TTH, Wolbers M, Mai PP, Dung NT, Mai NH, et al.: Combination Antifungal Therapy for Cryptococcal Meningitis. N Engl J Med 2013, 368(14):1291-302.
• [50]De Ruyter JC, Olthof MR, Seidell JC, Katan MB: A Trial of Sugar-free or Sugar-Sweetened Beverages and Body Weight in Children. N Engl J Med 2012, 367(15):1397-406.
• [51]El Barzouhi A, Vleggeert-Lankamp C, Nijeholt L à, Geert J, Van DK, Van DH, et al.: Magnetic Resonance Imaging in Follow-up Assessment of Sciatica. N Engl J Med 2013, 368(11):999-1007.
• [52]Farooq V, van Klaveren D, Steyerberg EW, Meliga E, Vergouwe Y, Chieffo A, et al.: Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II. Lancet 2013, 381(9867):639-50.
• [53]Feldman T, Foster E, Glower DD, Kar S, Rinaldi MJ, Fail PS, et al.: Percutaneous Repair or Surgery for Mitral Regurgitation. N Engl J Med 2011, 364(15):1395-406.
• [54]Free C, Knight R, Robertson S, Whittaker R, Edwards P, Zhou W, et al.: Smoking cessation support delivered via mobile phone text messaging (txt2stop): A single-blind, randomised trial. Lancet 2011, 378(9785):49-55.
• [55]Funk LM, Weiser TG, Berry WR, Lipsitz SR, Merry AF, Enright AC, et al.: Global operating theatre distribution and pulse oximetry supply: An estimation from reported data. Lancet 2010, 376(9746):1055-61.
• [56]Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, et al.: Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 2011, 377(9774):1341-52.
• [57]Gebre T, Ayele B, Zerihun M, Genet A, Stoller NE, Zhou Z, et al.: Comparison of annual versus twice-yearly mass azithromycin treatment for hyperendemic trachoma in Ethiopia: a cluster-randomised trial. Lancet 2012, 379(9811):143-51.
• [58]Gill TM, Gahbauer EA, Han L, Allore HG: Trajectories of Disability in the Last Year of Life. N Engl J Med 2010, 362(13):1173-80.
• [59]Girotra S, Nallamothu BK, Spertus JA, Li Y, Krumholz HM, Chan PS: Trends in Survival after In-Hospital Cardiac Arrest. N Engl J Med 2012, 367(20):1912-20.
• [60]Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero J, Vargas-Vasquez D, et al.: Delamanid for Multidrug-Resistant Pulmonary Tuberculosis. N Engl J Med 2012, 366(23):2151-60.
• [61]Green J, Charman T, McConachie H, Aldred C, Slonims V, Howlin P, et al.: Parent-mediated communication-focused treatment in children with autism (PACT): a randomised controlled trial. Lancet 2010, 375(9732):2152-60.
• [62]Green RC, Roberts JS, Cupples LA, Relkin NR, Whitehouse PJ, Brown T, et al.: Disclosure of APOE Genotype for Risk of Alzheimer’s Disease. N Engl J Med 2009, 361(3):245-54.
• [63]Gupta J, Kai J, Middleton L, Pattison H, Gray R, Daniels J: Levonorgestrel intrauterine system versus medical therapy for menorrhagia. N Engl J Med 2013, 368(2):128-37.
• [64]Gutiérrez OM, Mannstadt M, Isakova T, Rauh-Hain J, Tamez H, Shah A, et al.: Fibroblast Growth Factor 23 and Mortality among Patients Undergoing Hemodialysis. N Engl J Med 2008, 359(6):584-92.
• [65]Hanney M, Prasher V, Williams N, Jones EL, Aarsland D, Corbett A, et al.: Memantine for dementia in adults older than 40 years with Down’s syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet 2012, 379(9815):528-36.
• [66]Hegarty K, O’Doherty L, Taft A, Chondros P, Brown S, Valpied J, et al.: Screening and counselling in the primary care setting for women who have experienced intimate partner violence (WEAVE): a cluster randomised controlled trial. Lancet 2013, 382(9888):249-58.
• [67]Hill JC, Whitehurst DG, Lewis M, Bryan S, Dunn KM, Foster NE, et al.: Comparison of stratified primary care management for low back pain with current best practice (STarT Back): a randomised controlled trial. Lancet 2011, 378(9802):1560-71.
• [68]Holman RR, Farmer AJ, Davies MJ, Levy JC, Darbyshire JL, Keenan JF, et al.: Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med 2009, 361(18):1736-47.
• [69]Hunt LP, Ben-Shlomo Y, Clark EM, Dieppe P, Judge A, MacGregor AJ, et al.: 90-day mortality after 409 096 total hip replacements for osteoarthritis, from the National Joint Registry for England and Wales: a retrospective analysis. The Lancet 2013, 382(9898):1097-104.
• [70]Jabre P, Belpomme V, Azoulay E, Jacob L, Bertrand L, Lapostolle F, et al.: Family Presence during Cardiopulmonary Resuscitation. N Engl J Med 2013, 368(11):1008-18.
• [71]Jacobs AK, Normand ST, Massaro JM, Cutlip DE, Carrozza JP, Marks AD, et al.: Nonemergency PCI at Hospitals with or without On-Site Cardiac Surgery. N Engl J Med 2013, 368(16):1498-508.
• [72]Katz J, Lee AC, Kozuki N, Lawn JE, Cousens S, Blencowe H, et al.: Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis. Lancet 2013, 382(9890):417-25.
• [73]Kelly HW, Sternberg AL, Lescher R, Fuhlbrigge AL, Williams P, Zeiger RS, et al.: Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012, 367(10):904-12.
• [74]Kessler D, Lewis G, Kaur S, Wiles N, King M, Weich S, et al.: Therapist-delivered internet psychotherapy for depression in primary care: a randomised controlled trial. Lancet 2009, 374(9690):628-34.
• [75]King G, Gakidou E, Imai K, Lakin J, Moore RT, Nall C, et al.: Public policy for the poor? A randomised assessment of the Mexican universal health insurance programme. Lancet 2009, 373(9673):1447-54.
• [76]Kinmonth A, Wareham NJ, Hardeman W, Sutton S, Prevost AT, Fanshawe T, et al.: Efficacy of a theory-based behavioural intervention to increase physical activity in an at-risk group in primary care (ProActive UK): a randomised trial. Lancet 2008, 371(9606):41-8.
• [77]Kirby MJ, Ameh D, Bottomley C, Green C, Jawara M, Milligan PJ, et al.: Effect of two different house screening interventions on exposure to malaria vectors and on anaemia in children in The Gambia: a randomised controlled trial. Lancet 2009, 374(9694):998-1009.
• [78]Labrie J, Berghmans BLCM, Fischer K, Milani AL, Van DW, Smalbraak DJC, et al.: Surgery versus Physiotherapy for Stress Urinary Incontinence. N Engl J Med 2013, 369(12):1124-33.
• [79]Lamb SE, Marsh JL, Hutton JL, Nakash R, Cooke MW: Mechanical supports for acute, severe ankle sprain: a pragmatic, multicentre, randomised controlled trial. Lancet 2009, 373(9663):575-81.
• [80]Lamb SE, Gates S, Williams MA, Williamson EM, Mt-Isa S, Withers EJ, et al.: Emergency department treatments and physiotherapy for acute whiplash: A pragmatic, two-step, randomised controlled trial. Lancet 2013, 381(9866):546-56.
• [81]Lamb SE, Hansen Z, Lall R, Castelnuovo E, Withers EJ, Nichols V, et al.: Group cognitive behavioural treatment for low-back pain in primary care: a randomised controlled trial and cost-effectiveness analysis. Lancet 2010, 375(9718):916-23.
• [82]Lawlor DA, Wills AK, Fraser A, Sayers A, Fraser WD, Tobias JH: Association of maternal vitamin D status during pregnancy with bone-mineral content in offspring: a prospective cohort study. Lancet 2013, 381(9884):2176-83.
• [83]Lester RT, Ritvo P, Mills EJ, Kariri A, Karanja S, Chung MH, et al.: Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet 2010, 376(9755):1838-45.
• [84]Lidegaard Ø, Løkkegaard E, Jensen A, Skovlund CW, Keiding N: Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med 2012, 366(24):2257-66.
• [85]Liem S, Schuit E, Hegeman M, Bais J, De Boer K, Bloemenkamp K, et al.: Cervical pessaries for prevention of preterm birth in women with a multiple pregnancy (ProTWIN): a multicentre, open-label randomised controlled trial. Lancet 2013, 382(9901):1341-9.
• [86]Lim SS, Stein DB, Charrow A, Murray CJ: Tracking progress towards universal childhood immunisation and the impact of global initiatives: a systematic analysis of three-dose diphtheria, tetanus, and pertussis immunisation coverage. Lancet 2008, 372(9655):2031-46.
• [87]Lo AC, Guarino PD, Richards LG, Haselkorn JK, Wittenberg GF, Federman DG, et al.: Robot-Assisted Therapy for Long-Term Upper-Limb Impairment after Stroke. N Engl J Med 2010, 362(19):1772-83.
• [88]Lorenz MW, Polak JF, Kavousi M, Mathiesen EB, Völzke H, Tuomainen T, et al.: Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): A meta-analysis of individual participant data. Lancet 2012, 379(9831):2053-62.
• [89]Lu C, Schneider MT, Gubbins P, Leach-Kemon K, Jamison D, Murray CJ: Public financing of health in developing countries: a cross-national systematic analysis. Lancet 2010, 375(9723):1375-87.
• [90]Marcus CL, Moore RH, Rosen CL, Giordani B, Garetz SL, Taylor HG, et al.: A Randomized Trial of Adenotonsillectomy for Childhood Sleep Apnea. N Engl J Med 2013, 368(25):2366-76.
• [91]Martin DF, Maguire MG, Ying G, Grunwald JE, Fine SL, Jaffe GJ: Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011, 364(20):1897-908.
• [92]Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A, Strand T, et al.: Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes. N Engl J Med 2009, 361(1):40-51.
• [93]May M, Boulle A, Phiri S, Messou E, Myer L, Wood R, et al.: Prognosis of patients with HIV-1 infection starting antiretroviral therapy in sub-Saharan Africa: A collaborative analysis of scale-up programmes. Lancet 2010, 376(9739):449-57.
• [94]McManus RJ, Mant J, Bray EP, Holder R, Jones MI, Greenfield S, et al.: Telemonitoring and self-management in the control of hypertension (TASMINH2): a randomised controlled trial. Lancet 2010, 376(9736):163-72.
• [95]Melhuish E, Belsky J, Leyland AH, Barnes J: Effects of fully-established Sure Start Local Programmes on 3-year-old children and their families living in England: a quasi-experimental observational study. Lancet 2008, 372(9650):1641-7.
• [96]Milstone AM, Elward A, Song X, Zerr DM, Orscheln R, Speck K, et al.: Daily chlorhexidine bathing to reduce bacteraemia in critically ill children: a multicentre, cluster-randomised, crossover trial. Lancet 2013, 381(9872):1099-106.
• [97]Montalescot G, Zeymer U, Silvain J, Boulanger B, Cohen M, Goldstein P, et al.: Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial. Lancet 2011, 378(9792):693-703.
• [98]Mozaffarian D, Shi P, Morris JS, Spiegelman D, Grandjean P, Siscovick DS, et al.: Mercury Exposure and Risk of Cardiovascular Disease in Two U.S. Cohorts. N Engl J Med 2011, 364(12):1116-25.
• [99]Odd DE, Lewis G, Whitelaw A, Gunnell D: Resuscitation at birth and cognition at 8 years of age: a cohort study. Lancet 2009, 373(9675):1615-22.
• [100]Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, et al.: A Double-Blind, Delayed-Start Trial of Rasagiline in Parkinson’s Disease. N Engl J Med 2009, 361(13):1268-78.
• [101]Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, et al.: Long-Term Cognitive Impairment after Critical Illness. N Engl J Med 2013, 369(14):1306-16.
• [102]Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, et al.: Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet 2010, 376(9757):2009-17.
• [103]Patel V, Weiss HA, Chowdhary N, Naik S, Pednekar S, Chatterjee S, et al.: Effectiveness of an intervention led by lay health counsellors for depressive and anxiety disorders in primary care in Goa, India (MANAS): a cluster randomised controlled trial. Lancet 2010, 376(9758):2086-95.
• [104]Peek M, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, et al.: Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009, 374(9698):1351-63.
• [105]Pimentel M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, et al.: Rifaximin Therapy for Patients with Irritable Bowel Syndrome without Constipation. N Engl J Med 2011, 364(1):22-32.
• [106]Price D, Musgrave SD, Shepstone L, Hillyer EV, Sims EJ, Gilbert RFT, et al.: Leukotriene Antagonists as First-Line or Add-on Asthma-Controller Therapy. N Engl J Med 2011, 364(18):1695-707.
• [107]Pronyk PM, Muniz M, Nemser B, Somers M, McClellan L, Palm CA, et al.: The effect of an integrated multisector model for achieving the Millennium Development Goals and improving child survival in rural sub-Saharan Africa: A non-randomised controlled assessment. Lancet 2012, 379(9832):2179-88.
• [108]Puhan MA, Garcia-Aymerich J, Frey M, ter Riet G, Antó JM, Agustí AG, et al.: Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index. Lancet 2009, 374(9691):704-11.
• [109]Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M, et al.: Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 2012, 379(9827):1705-11.
• [110]Sitas F, Egger S, Bradshaw D, Groenewald P, Laubscher R, Kielkowski D, et al.: Differences among the coloured, white, black, and other South African populations in smoking-attributed mortality at ages 35–74 years: a case–control study of 481 640 deaths. Lancet 2013, 382(9893):685-93.
• [111]Smith KR, McCracken JP, Weber MW, Hubbard A, Jenny A, Thompson LM, et al.: Effect of reduction in household air pollution on childhood pneumonia in Guatemala (RESPIRE): A randomised controlled trial. Lancet 2011, 378(9804):1717-26.
• [112]Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al.: The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012, 380(9851):1387-95.
• [113]Sommers BD, Baicker K, Epstein AM: Mortality and access to care among adults after state medicaid expansions. N Engl J Med 2012, 367(11):1025-34.
• [114]Stanworth SJ, Estcourt LJ, Powter G, Kahan BC, Dyer C, Choo L, et al.: A No-Prophylaxis Platelet-Transfusion Strategy for Hematologic Cancers. N Engl J Med 2013, 368(19):1771-80.
• [115]Sterne J, May M, Costagliola D, De Wolf F, Phillips AN, Harris R, et al.: Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet 2009, 373(9672):1352-63.
• [116]Strang J, Metrebian N, Lintzeris N, Potts L, Carnwath T, Mayet S, et al.: Supervised injectable heroin or injectable methadone versus optimised oral methadone as treatment for chronic heroin addicts in England after persistent failure in orthodox treatment (RIOTT): a randomised trial. Lancet 2010, 375(9729):1885-95.
• [117]Subak LL, Wing R, West DS, Franklin F, Vittinghoff E, Creasman JM, et al.: Weight Loss to Treat Urinary Incontinence in Overweight and Obese Women. N Engl J Med 2009, 360(5):481-90.
• [118]Tanser F, Bärnighausen T, Hund L, Garnett GP, McGrath N, Newell M: Effect of concurrent sexual partnerships on rate of new HIV infections in a high-prevalence, rural South African population: A cohort study. Lancet 2011, 378(9787):247-55.
• [119]Thabut G, Christie JD, Ravaud P, Castier Y, Brugière O, Fournier M, et al.: Survival after bilateral versus single lung transplantation for patients with chronic obstructive pulmonary disease: a retrospective analysis of registry data. Lancet 2008, 371(9614):744-51.
• [120]Underwood M, Lamb SE, Eldridge S, Sheehan B, Slowther A, Spencer A, et al.: Exercise for depression in elderly residents of care homes: a cluster-randomised controlled trial. Lancet 2013, 382(9886):41-9.
• [121]Vaucher YE, Peralta-Carcelen M, Finer NN, Carlo WA, Gantz MG, Walsh MC, et al.: Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial. N Engl J Med 2012, 367(26):2495-504.
• [122]Visco AG, Brubaker L, Richter HE, Nygaard I, Paraiso MFR, Menefee SA, et al.: Anticholinergic Therapy vs. OnabotulinumtoxinA for Urgency Urinary Incontinence. N Engl J Med 2012, 367(19):1803-13.
• [123]Wadden TA, Volger S, Sarwer DB, Vetter ML, Tsai AG, Berkowitz RI, et al.: A Two-Year Randomized Trial of Obesity Treatment in Primary Care Practice. N Engl J Med 2011, 365(21):1969-79.
• [124]Walkup JT, Albano AM, Piacentini J, Birmaher B, Compton SN, Sherrill JT, et al.: Cognitive Behavioral Therapy, Sertraline, or a Combination in Childhood Anxiety. N Engl J Med 2008, 359(26):2753-66.
• [125]Walz G, Budde K, Mannaa M, Nürnberger J, Wanner C, Sommerer C, et al.: Everolimus in Patients with Autosomal Dominant Polycystic Kidney Disease. N Engl J Med 2010, 363(9):830-40.
• [126]Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Minniti CP, et al.: Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 2011, 377(9778):1663-72.
• [127]Weeks JC, Catalano PJ, Cronin A, Finkelman MD, Mack JW, Keating NL, et al.: Patients’ expectations about effects of chemotherapy for advanced cancer. N Engl J Med 2012, 367(17):1616-25.
• [128]Weintraub WS, Spertus JA, Kolm P, Maron DJ, Zhang Z, Jurkovitz C, et al.: Effect of PCI on Quality of Life in Patients with Stable Coronary Disease. N Engl J Med 2008, 359(7):677-87.
• [129]Weiser TG, Regenbogen SE, Thompson KD, Haynes AB, Lipsitz SR, Berry WR, et al.: An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet 2008, 372(9633):139-44.
• [130]Westerlund H, Kivimäki M, Singh-Manoux A, Melchior M, Ferrie JE, Pentti J, et al.: Self-rated health before and after retirement in France (GAZEL): a cohort study. Lancet 2009, 374(9705):1889-96.
• [131]Wherrett DK, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, et al.: Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet 2011, 378(9788):319-27.
• [132]Wiles N, Thomas L, Abel A, Ridgway N, Turner N, Campbell J, et al.: Cognitive behavioural therapy as an adjunct to pharmacotherapy for primary care based patients with treatment resistant depression: results of the CoBalT randomised controlled trial. Lancet 2013, 381(9864):375-84.
• [133]Yu H, Cowling BJ, Feng L, Lau EH, Liao Q, Tsang TK, et al.: Human infection with avian influenza A H7N9 virus: an assessment of clinical severity. Lancet 2013, 382(9887):138-45.
• [134]Zeig-Owens R, Webber MP, Hall CB, Schwartz T, Jaber N, Weakley J, et al.: Early assessment of cancer outcomes in New York City firefighters after the 9/11 attacks: an observational cohort study. Lancet 2011, 378(9794):898-905.
• [135]Gelman A, Van Mechelen I, Verbeke G, Heitjan DF, Meulders M: Multiple Imputation for Model Checking: Completed-Data Plots with Missing and Latent Data. Biometrics 2005, 1:74.
• [136]Abayomi K, Gelman A, Levy M: Diagnostics for multivariate imputations. J R Stat Soc: Ser C: Appl Stat 2008, 57(3):273-91.
• [137]He Y, Zaslavsky AM: Diagnosing imputation models by applying target analyses to posterior replicates of completed data. Stat Med 2012, 31(1):1-18.
• [138]Nguyen CD, Carlin JB, Lee KJ: Diagnosing problems with imputation models using the Kolmogorov-Smirnov test: a simulation study. BMC Med Res Methodol 2013, 13(1):1-18.