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Research, Methods, Statistics

Adjustment for Baseline Characteristics in Randomized Clinical Trials

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JAMA

Published Online: November 17, 2022

JAMA Guide to Statistics and Methods

Article Information and Disclosures

Mathias J. Holmberg, MD, MPH, PhD^1,2;

Lars W. Andersen, MD, MPH, PhD, DMSc^2,3,4

Author Affiliations

¹Department of Anesthesiology and Intensive Care, Randers Regional Hospital, Randers, Denmark
²Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
³Department of Anesthesiology and Intensive Care, Aarhus University Hospital, Aarhus, Denmark
⁴Prehospital Emergency Medical Services, Central Denmark Region, Denmark

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Original Investigation

Effect of Intravenous Treatment With a Balanced Solution vs Saline Solution on Mortality

Fernando G. Zampieri, MD, PhD; Flávia R. Machado, MD, PhD; Rodrigo S. Biondi, MD; Flávio G. R. Freitas, MD, PhD; Viviane C. Veiga, MD, PhD; Rodrigo C. Figueiredo, MD; Wilson J. Lovato, MD; Cristina P. Amêndola, MD, PhD; Ary Serpa-Neto, MD, PhD; Jorge L. R. Paranhos, MD; Marco A. V. Guedes, MD, PhD; Eraldo A. Lúcio, MD, PhD; Lúcio C. Oliveira-Júnior, MD; Thiago C. Lisboa, MD, PhD; Fábio H. Lacerda, MD; Israel S. Maia, MD; Cintia M. C. Grion, MD, PhD; Murillo S. C. Assunção, MD, PhD; Airton L. O. Manoel, MD, PhD; João M. Silva-Junior, MD, PhD; Péricles Duarte, MD; Rafael M. Soares, PhD; Tamiris A. Miranda, MSc; Lucas M. de Lima, IT; Rodrigo M. Gurgel, Biomed Sci; Denise M. Paisani, PhD; Thiago D. Corrêa, MD, PhD; Luciano C. P. Azevedo, MD, PhD; John A. Kellum, MD; Lucas P. Damiani, MSc; Nilton Brandão da Silva, MD, PhD; Alexandre B. Cavalcanti, MD, PhD; BaSICS investigators and the BRICNet members; Rodrigo Biondi; Renato B. Chaves; Amanda R. Santos; Vitor S. Barzilai; Flávio G. R. de Freitas; Nathaly F. Nunes; Rodrigo C. da Cunha; Elijane F. Alves; Rodrigo C. Figueiredo; Rodrigo B. Bortolini; Cintia L. Sartori; Eduardo S. Marques; Maria A de Sousa; Danieri Y. V. Tomotani; Airton L. O. Manoel; Wilson J. Lovato; Bruno G. Dantas; Leonardo C. Palma; Fábio L. da Silva; Cristina P. Amendola; Luciana C. Sanches; Fernanda A. M. Scuoteguazza; Ligia Z. de Britto; Ary Serpa Neto; Niklas S. Campos; Fabio B. Hohmann; Guilherme B. Olivato; Jorge L.R. Paranhos; Iany G. da Silva; Adilson de C. Meireles; Viviane C. Veiga; Juliana C. Coelho; Maiko M. Silveira; Agnes C. Lisboa; Marco A.V. Guedes; Luiz C.S. Passos; Daniela C. Dorta; Ramana A. Rangel; Péricles Duarte; Eraldo de A. Lúcio; Eduardo B. Tondo; Pablo A.A. Vaz; Paula K. de Oliveira; Lúcio C. de Oliveira Junior; Paulo H.P. Ferreira; Patrick H.S. Sampaio; Maurício G.S. Serra; Thiago C. Lisboa; Caroline Fachini; André P. Torelly; Alldren Souza; Fábio H. Lacerda; Eliana V. N. Martins; Bruno A.M.P. Besen; Carlos E. Brandão; João M. Silva Junior; Flávio W.F. Melo Junior; Flávio A. dos Santos; Israel S. Maia; Cássio L. Zandonai; Eduardo Berbigier; Cíntia M.C. Grion; Josiane Festti; Ana Luiza Mezzaroba; José Andrade; Marianne S. Camargo; Adriano F. Teixeira; José de S. Andrade Neto; Michele M.G. de Godoy; Andréia de F. T. de Mendonça; Mara L.F.S. Mendes; Renata C.I.C. Beltrão; Edson Romano; Marcelo L.P. Romano; Andre F. Costa; Jorge Farran; Felipe Dal-Pizzol; Danusa Damásio; Renata Gonçalves; Émerson B. da Silva; Luiz de F. Ferreira; Rafael L. da Costa; Kellen Lopes; Miquéias M.L. Silva; Douglas L.A.B. de Matos; Renata de A. Marques; Glauco A. Westphal; Miriam C. Machado; Juliano Ramos; Luiz M.S. Malbouisson; Bruno N. Lucena; Marlus M. Thompson; Lanese M. Figueiredo; Luana F. Mourão; Thiago S. Garces; Israel da S. Maia; Jaqueline F. Rohr; Fernanda Fontanela; Cassia P. B. Martins; Álvaro Rea Neto; Fernanda Reese; Mirella Oliveira; André L. N. Gobatto; Luciana S. de Mattos; Carolaine B. de Oliveira; Meton S. de Alencar Filho; Jussara A. Arraes; João G.T. Alves; Thiago C. De Morais; Antônio A. P. Fagundes Jr; Roberta T. Tallarico; Thais Coutinho; Ronald Torres; Fernando J.S. Ramos; Fernanda C. Athalla; Mauricio H.C. dos Santos; Paulo M.G. Nose; Cássia R. Shinotsuka; Pedro Kurtz; Bruno Guimarães; Luciana G. Pereira; Raquel B. Jupato; Bruno de A. Bravim; Marcos F. Knibel; Allan S. da Silva; Vinícius G. de Luca; Niklas Soderberg; Roseny dos R. Rodrigues; Luis E.P. Pfingsten; Cassiano Teixeira; José H.D. Barth; Giselle C. Pratini; Luiz Dalfior Junior; Márcio H. Kai; Sérgio Blecher; Hugo C. A. Urbano; Lucas L. Carvalho; Danielle C. A. Moreira; Ana L. S. Bernardes; Vandack A. Nobre Júnior; Paula F. Vassallo; Cecília G. Ravetti; Ho Y. Li; Vivian V. T. Sales; Renata Guazzelli; Rafael D. de Oliveira; Leandro Pozzo; Leandro U. Taniguchi; Pedro V. Mendes; Suzana M. A. Lobo; Miriam Machado; Ana B. B. Camacho; Pablo O. Tomba; Fred C. T. Lizidatti; Walter C. G. Baptista; Aline R. Moreira; Manoela M. de Sousa; Marcelo O. Santos; Karla Moretto; Priscilla A. de Martins; Liz M. L. de Souza; Thiago R. Sequeira; Manoel M. S. Pedrinha; Marcone L. S. da Rocha; Francisco R. V. Saleiro; Tatiana M. Clementino; Hélio P. Guimarães; Marcos C. R. Mello; Mirella C. de Oliveira; Fernanda B. Reese; Denise M. Ferreira; Fernanda A. F. Gonçalves; Roberta M. L. Roepke; Bruno M. Tomazini; Sidiner M. Vaz; Miria Bonjour Laviola; Thiago D. Correa; Roger M. Alencar; Denise N. Freitas; Heitor P. Póvoas Filho; Liliane B. S. Passos; Juliane de M. Silva
JAMA Guide to Statistics and Methods

Estimands, Estimators, and Estimates

Roderick J. Little, PhD; Roger J. Lewis, MD, PhD

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The purpose of randomization in clinical trials is to ensure that there are no systematic differences between treatment groups with respect to measured and unmeasured baseline characteristics that could influence the outcome of interest.¹ In a randomized clinical trial (RCT) without selection or information bias, an unadjusted analysis (ie, an analysis that does not take baseline characteristics into account) will provide unbiased estimates of treatment effects.

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Article Information

Corresponding Author: Lars W. Andersen, MD, MPH, PhD, DMSc, Department of Anesthesiology and Intensive Care, Aarhus University Hospital, Nørrebrogade 44, Aarhus, NA 8000, Denmark (lwandersen@clin.au.dk).

Published Online: November 17, 2022. doi:10.1001/jama.2022.21506

Conflict of Interest Disclosures: None reported.

Disclaimer: Dr Andersen is a statistical reviewer for JAMA but was not involved in any of the decisions regarding review of the manuscript or its acceptance.

References

Broglio K . Randomization in clinical trials: permuted blocks and stratification. JAMA. 2018;319(21):2223-2224. doi:10.1001/jama.2018.6360 PubMed Google Scholar Crossref

US Food and Drug Administration. Adjusting for covariates in randomized clinical trials for drugs and biological products. Accessed November 8, 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/adjusting-covariates-randomized-clinical-trials-drugs-and-biological-products

European Medicines Agency. Guidelines on adjustment for baseline covariates in clinical trials. Accessed November 8, 2022. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-adjustment-baseline-covariates-clinical-trials_en.pdf

Pirondini L , Gregson J , Owen R , Collier T , Pocock S . Covariate adjustment in cardiovascular randomized controlled trials: its value, current practice, and need for improvement. JACC Heart Fail. 2022;10(5):297-305. doi:10.1016/j.jchf.2022.02.007 PubMed Google Scholar Crossref

Zampieri FG , Machado FR , Biondi RS , et al; BaSICS investigators and the BRICNet members. Effect of intravenous fluid treatment with a balanced solution vs 0.9% saline solution on mortality in critically ill patients: the BaSICS randomized clinical trial. JAMA. 2021;326(9):818-829. doi:10.1001/jama.2021.11684 PubMed Google Scholar Crossref

Mistry EA , Yeatts SD , Khatri P , et al. National Institutes of Health Stroke Scale as an outcome in stroke research: value of ANCOVA over analyzing change from baseline. Stroke. 2022;53(4):e150-e155. doi:10.1161/STROKEAHA.121.034859 Google Scholar Crossref

Morris TP , Walker AS , Williamson EJ , White IR . Planning a method for covariate adjustment in individually randomised trials: a practical guide. Trials. 2022;23(1):328. doi:10.1186/s13063-022-06097-z PubMed Google Scholar Crossref

Localio AR , Berlin JA , Ten Have TR , Kimmel SE . Adjustments for center in multicenter studies: an overview. Ann Intern Med. 2001;135(2):112-123. doi:10.7326/0003-4819-135-2-200107170-00012 PubMed Google Scholar Crossref

Kahan BC , Jairath V , Doré CJ , Morris TP . The risks and rewards of covariate adjustment in randomized trials: an assessment of 12 outcomes from 8 studies. Trials. 2014;15:139. doi:10.1186/1745-6215-15-139 PubMed Google Scholar Crossref

Little RJ , Lewis RJ . Estimands, estimators, and estimates. JAMA. 2021;326(10):967-968. doi:10.1001/jama.2021.2886 PubMed Google Scholar Crossref

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