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Research, Methods, Statistics

Target Trial EmulationA Framework for Causal Inference From Observational Data

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JAMA

Published Online: December 12, 2022

JAMA Guide to Statistics and Methods

Article Information and Disclosures

Miguel A. Hernán, MD, DrPH¹;

Wei Wang, PhD²;

David E. Leaf, MD, MMSc³

Author Affiliations

¹CAUSALab, Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
²Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, Massachusetts
³Division of Renal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

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Original Investigation

Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19

Shruti Gupta, MD, MPH; Wei Wang, PhD; Salim S. Hayek, MD; Lili Chan, MD, MSCR; Kusum S. Mathews, MD, MPH, MSCR; Michal L. Melamed, MD, MHS; Samantha K. Brenner, MD, MPH; Amanda Leonberg-Yoo, MD, MS; Edward J. Schenck, MD, MS; Jared Radbel, MD; Jochen Reiser, MD, PhD; Anip Bansal, MD; Anand Srivastava, MD, MPH; Yan Zhou, MD; Diana Finkel, DO; Adam Green, MD, MBA; Mary Mallappallil, MD; Anthony J. Faugno, MD; Jingjing Zhang, MD, PhD; Juan Carlos Q. Velez, MD; Shahzad Shaefi, MD, MPH; Chirag R. Parikh, MD, PhD; David M. Charytan, MD, MSc; Ambarish M. Athavale, MBBS, MD; Allon N. Friedman, MD; Roberta E. Redfern, PhD; Samuel A. P. Short, BA; Simon Correa, MD, MMSc; Kapil K. Pokharel, MBBS; Andrew J. Admon, MD, MPH, MSc; John P. Donnelly, PhD; Hayley B. Gershengorn, MD; David J. Douin, MD; Matthew W. Semler, MD; Miguel A. Hernán, MD, DrPH; David E. Leaf, MD, MMSc; STOP-COVID Investigators; Carl P. Walther; Samaya J. Anumudu; Justin Arunthamakun; Kathleen F. Kopecky; Gregory P. Milligan; Peter A. McCullough; Thuy-Duyen Nguyen; Shahzad Shaefi; Megan L. Krajewski; Sidharth Shankar; Ameeka Pannu; Juan D. Valencia; Sushrut S. Waikar; Zoe A. Kibbelaar; Ambarish M. Athavale; Peter Hart; Shristi Upadhyay; Ishaan Vohra; Ajiboye Oyintayo; Adam Green; Jean-Sebastien Rachoin; Christa A. Schorr; Lisa Shea; Daniel L. Edmonston; Christopher L. Mosher; Alexandre M. Shehata; Zaza Cohen; Valerie Allusson; Gabriela Bambrick-Santoyo; Noor ul aain Bhatti; Bijal Mehta; Aquino Williams; Samantha K. Brenner; Patricia Walters; Ronaldo C. Go; Keith M. Rose; Miguel A. Hernán; Rebecca Lisk; Amy M. Zhou; Ethan C. Kim; Lili Chan; Kusum S. Mathews; Steven G. Coca; Deena R. Altman; Aparna Saha; Howard Soh; Huei Hsun Wen; Sonali Bose; Emily A. Leven; Jing G. Wang; Gohar Mosoyan; Girish N. Nadkarni; Pattharawin Pattharanitima; Emily J. Gallagher; Allon N. Friedman; John Guirguis; Rajat Kapoor; Christopher Meshberger; Katherine J. Kelly; Chirag R. Parikh; Brian T. Garibaldi; Celia P. Corona-Villalobos; Yumeng Wen; Steven Menez; Rubab F. Malik; Carmen Elena Cervantes; Samir C. Gautam; Mary C. Mallappallil; Jie Ouyang; Sabu John; Ernie Yap; Yohannes Melaku; Ibrahim Mohamed; Siddhartha Bajracharya; Isha Puri; Mariah Thaxton; Jyotsna Bhattacharya; John Wagner; Leon Boudourakis; H. Bryant Nguyen; Afshin Ahoubim; Kianoush Kashani; Shahrzad Tehranian; Leslie F. Thomas; Dheeraj Reddy Sirganagari; Pramod K. Guru; Yan Zhou; Paul A. Bergl; Jesus Rodriguez; Jatan A. Shah; Mrigank S. Gupta; Princy N. Kumar; Deepa G. Lazarous; Seble G. Kassaye; Michal L. Melamed; Tanya S. Johns; Ryan Mocerino; Kalyan Prudhvi; Denzel Zhu; Rebecca V. Levy; Yorg Azzi; Molly Fisher; Milagros Yunes; Kaltrina Sedaliu; Ladan Golestaneh; Maureen Brogan; Neelja Kumar; Michael Chang; Jyotsana Thakkar; Ritesh Raichoudhury; Akshay Athreya; Mohamed Farag; Edward J. Schenck; Soo Jung Cho; Maria Plataki; Sergio L. Alvarez-Mulett; Luis G. Gomez-Escobar; Di Pan; Stefi Lee; Jamuna Krishnan; William Whalen; David Charytan; Ashley Macina; Sobaata Chaudhry; Benjamin Wu; Frank Modersitzki; Anand Srivastava; Alexander S. Leidner; Carlos Martinez; Jacqueline M. Kruser; Richard G. Wunderink; Alexander J. Hodakowski; Juan Carlos Q. Velez; Eboni G. Price-Haywood; Luis A. Matute-Trochez; Anna E. Hasty; Muner MB. Mohamed; Rupali S. Avasare; David Zonies; David E. Leaf; Shruti Gupta; Meghan E. Sise; Erik T. Newman; Samah Abu Omar; Kapil K. Pokharel; Shreyak Sharma; Harkarandeep Singh; Simon Correa; Tanveer Shaukat; Omer Kamal; Wei Wang; Heather Yang; Jeffery O. Boateng; Meghan Lee; Ian A. Strohbehn; Jiahua Li; Ariel L. Mueller; Roberta E. Redfern; Nicholas S. Cairl; Gabriel Naimy; Abeer Abu-Saif; Danyell Hall; Laura Bickley; Chris Rowan; Farah Madhani-Lovely; Vasil Peev; Jochen Reiser; John J. Byun; Andrew Vissing; Esha M. Kapania; Zoe Post; Nilam P. Patel; Joy-Marie Hermes; Anne K. Sutherland; Amee Patrawalla; Diana G. Finkel; Barbara A. Danek; Sowminya Arikapudi; Jeffrey M. Paer; Peter Cangialosi; Mark Liotta; Jared Radbel; Sonika Puri; Jag Sunderram; Matthew T. Scharf; Ayesha Ahmed; Ilya Berim; Jayanth S. Vatson; Shuchi Anand; Joseph E. Levitt; Pablo Garcia; Suzanne M. Boyle; Rui Song; Ali Arif; Jingjing Zhang; Sang Hoon Woo; Xiaoying Deng; Goni Katz-Greenberg; Katharine Senter; Moh’d A. Sharshir; Vadym V. Rusnak; Muhammad Imran Ali; Terri Peters; Kathy Hughes; Anip Bansal; Amber S. Podoll; Michel Chonchol; Sunita Sharma; Ellen L. Burnham; David J. Douin; Arash Rashidi; Rana Hejal; Eric Judd; Laura Latta; Ashita Tolwani; Timothy E. Albertson; Jason Y. Adams; Steven Y. Chang; Rebecca M. Beutler; Carl E. Schulze; Etienne Macedo; Harin Rhee; Kathleen D. Liu; Vasantha K. Jotwani; Jay L. Koyner; Chintan V. Shah; Vishal Jaikaransingh; Stephanie M. Toth-Manikowski; Min J. Joo; James P. Lash; Javier A. Neyra; Nourhan Chaaban; Madona Elias; Yahya Ahmad; Alfredo Iardino; Elizabeth H. Au; Jill H. Sharma; Marie Anne Sosa; Sabrina Taldone; Gabriel Contreras; David De La Zerda; Alessia Fornoni; Hayley B. Gershengorn; Salim S. Hayek; Pennelope Blakely; Hanna Berlin; Tariq U. Azam; Husam Shadid; Michael Pan; Patrick O’ Hayer; Chelsea Meloche; Rafey Feroze; Kishan J. Padalia; Abbas Bitar; Jeff Leya; John P. Donnelly; Andrew J. Admon; Jennifer E. Flythe; Matthew J. Tugman; Emily H. Chang; Brent R. Brown; Amanda K. Leonberg-Yoo; Ryan C. Spiardi; Todd A. Miano; Meaghan S. Roche; Charles R. Vasquez; Amar D. Bansal; Natalie C. Ernecoff; Sanjana Kapoor; Siddharth Verma; Huiwen Chen; Csaba P. Kovesdy; Miklos Z. Molnar; Ambreen Azhar; S. Susan Hedayati; Mridula V. Nadamuni; Shani Shastri; Duwayne L. Willett; Samuel A.P. Short; Amanda D. Renaghan; Kyle B. Enfield; Pavan K. Bhatraju; A. Bilal Malik; Matthew W. Semler; Anitha Vijayan; Christina Mariyam Joy; Tingting Li; Seth Goldberg; Patricia F. Kao; Greg L. Schumaker; Nitender Goyal; Anthony J. Faugno; Caroline M. Hsu; Asma Tariq; Leah Meyer; Ravi K. Kshirsagar; Aju Jose; Daniel E. Weiner; Marta Christov; Jennifer Griffiths; Sanjeev Gupta; Aromma Kapoor; Perry Wilson; Tanima Arora; Ugochukwu Ugwuowo

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Quantifying the effect of a treatment on a clinical outcome—causal inference—requires the comparison of outcomes under different courses of action. For example, to quantify the effect of tocilizumab on mortality in critically ill patients with COVID-19, the mortality risk could be compared between a group of patients administered tocilizumab and a group who are not. Ideally, eligible patients would be assigned to these groups at random. The key advantage of such a randomized trial is that both groups are expected to be comparable, and thus any differences in mortality can be attributed to tocilizumab rather than to prognostic differences between the groups.

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Article Information

Corresponding Author: Miguel Hernán, MD, DrPH, Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA 02115 (miguel_hernan@post.harvard.edu).

Published Online: December 12, 2022. doi:10.1001/jama.2022.21383

Conflict of Interest Disclosures: Dr Hernán reported receiving grants from the National Institutes of Health (NIH); serving as data science adviser for ProPublica; and serving as a consultant for Cytel. Dr Leaf reported receiving grants from the NIH (R01HL144566, R01DK125786). No other disclosures were reported.

References

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Gupta S , Wang W , Hayek SS , et al; STOP-COVID Investigators. Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19. JAMA Intern Med. 2021;181(1):41-51. doi:10.1001/jamainternmed.2020.6252 PubMed Google Scholar Crossref

Yadav K , Lewis RJ . Immortal time bias in observational studies. JAMA. 2021;325(7):686-687. doi:10.1001/jama.2020.9151 PubMed Google Scholar Crossref

Hernán MA , Sauer BC , Hernández-Díaz S , Platt R , Shrier I . Specifying a target trial prevents immortal time bias and other self-inflicted injuries in observational analyses. J Clin Epidemiol. 2016;79:70-75. doi:10.1016/j.jclinepi.2016.04.014 PubMed Google Scholar Crossref

Hernán MA , Alonso A , Logan R , et al. Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease. Epidemiology. 2008;19(6):766-779. doi:10.1097/EDE.0b013e3181875e61 PubMed Google Scholar Crossref

Stensrud MJ , Valberg M , Røysland K , Aalen OO . Exploring selection bias by causal frailty models: the magnitude matters. Epidemiology. 2017;28(3):379-386. doi:10.1097/EDE.0000000000000621 PubMed Google Scholar Crossref

Adler AI , Latimer NR . Adjusting for nonadherence or stopping treatments in randomized clinical trials. JAMA. 2021;325(20):2110-2111. doi:10.1001/jama.2021.2433 PubMed Google Scholar Crossref

Gordon AC , Mouncey PR , Al-Beidh F , et al; REMAP-CAP Investigators. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021;384(16):1491-1502. doi:10.1056/NEJMoa2100433 PubMed Google Scholar Crossref

Haukoos JS , Lewis RJ . The propensity score. JAMA. 2015;314(15):1637-1638. doi:10.1001/jama.2015.13480 PubMed Google Scholar Crossref

Hernán MA . The hazards of hazard ratios. Epidemiology. 2010;21(1):13-15. doi:10.1097/EDE.0b013e3181c1ea43 PubMed Google Scholar Crossref

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