Methods for randomized, blinded, controlled evaluation of putative disease interventions in multilaboratory, preclinical assessment networks
Science faces a reproducibility crisis, and public trust in science declines when large clinical trials, which had been qualified by promising preclinical studies, fail. While some clinical trial designs may have been inadequate, preclinical assessments of disease interventions might have lacked key elements of rigor such as treatment concealment, randomization, blinded outcomes, prespecified and adequate sample sizes, and models including comorbidities. Here, to demonstrate feasibility and practicality of enhanced rigor in preclinical assessment, we designed a six-laboratory network that implemented rigorous study elements, using acute ischemic stroke for demonstration. This network enrolled 2,615 rodents in 5 different models and implemented a multistage, multiarm statistical design that sequentially eliminated candidate interventions during interim analyses. The methods included centralized intervention packaging, randomization, data quality assessment and data archiving. Blinded analysis of 9,274 video-recorded behavioral tasks and 3,652 magnetic resonance images were evaluated. All tools and protocols are presented and could be adapted to preclinical assessment in other disease areas.
Authors
- Kazi Akhter (ORCID: https://orcid.org/0009-0001-6390-183X)
- Andrew L.S. Goh
- Jun Wang (ORCID: https://orcid.org/0000-0001-7564-2364)
- Songze Li (ORCID: https://orcid.org/0000-0003-3168-644X)
- Louise D. McCullough (ORCID: https://orcid.org/0000-0002-8050-1686)
- Guanghua Sun (ORCID: https://orcid.org/0000-0002-3884-3826)
- Jessica S. Lamb (ORCID: https://orcid.org/0000-0002-0342-9983)
- Lidiya Obertas
- Kristofer Wood (ORCID: https://orcid.org/0000-0002-1020-7860)
- Patrick Lyden
- Michael E Maniskas (ORCID: https://orcid.org/0000-0002-9250-4585)
- J.B. Mandeville
- F Hyder
- Sofia Evelyn Velazquez
- Ryan P. Cabeen (ORCID: https://orcid.org/0000-0002-1372-3588)
- Conor W. Johnson (ORCID: https://orcid.org/0000-0002-0915-6496)
- Frank W. Blixt (ORCID: https://orcid.org/0000-0002-5293-8223)
- Ali Herman
- Adnan Bibic (ORCID: https://orcid.org/0000-0001-8044-2906)
- Brooklyn D. Avery (ORCID: https://orcid.org/0009-0009-7093-7580)
- Sungjin Kim (ORCID: https://orcid.org/0009-0005-7738-4895)
- Anjali Chauhan (ORCID: https://orcid.org/0000-0002-9825-8100)
- Tao Qin (ORCID: https://orcid.org/0009-0006-2511-8373)
- Steve R Zeiler
- Sebastian Diaz
- Shahneela Siddiqui
- Dan Thedens
- Shuning Huang
- Javier Allende Labastida
- Eng H. Lo
- Hannah Beatty
- Ali Arbab
- Rakesh B. Patel
- Lili Yu
- Takahiko Imai
- Ligia Boisserand
- Klaus van Leyen
- Diego Motales-Scheihing
- Brijesh Sutariya
- David C. Hess
- Shun-Mug Ting
- Peter Van Zijl
- Andreia Morais
- Andre Rogatko
- Jaroslaw Aronowski
- Anil K. Chauhan
- Senthilkumar Karuppagounder
- Nirav Dhanesha
- Steven Lannon
- Marcio A. Diniz
- Emma Imakavar
- Yanrong Shi
- Mohammad Badruzzaman Khan
- Raymond Koehler
- Cenk Ayata
- Karen L. Crawford
- Jiadi Xu
- Enrique C. Leira
- Cameron Smith
- Kris Dhandapani
- Ken Arai
- Nicholas Wilder
- Mariia Kumskova
- Lauren Sansing
- Marian Cabrera-Ayala
- Mohammad Nisar
- Valina Dawson
- Xuyan Jin
- Karisma Nagarkatti
- Monica Estrada
- Suyi Cao
- Basavaraju Sanganahilli Ganganna
- Taylan Erodogan
- W. Taylor Kimberly
- Steward Niefert
Institutions
- University of Iowa (US)
- Cedars-Sinai Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Johns Hopkins University (US)
- Augusta University (US)
- Johns Hopkins Medicine (US)
- Keck Hospital of USC (US)
- Yale University (US)
- Massachusetts General Hospital (US)
- The University of Texas Health Science Center (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Lab Animal
- Published
- 2026-02-18
- DOI
- https://doi.org/10.1038/s41684-026-01683-z
- Primary Topic
- Acute Ischemic Stroke Management
- Type
- article
- Field-Weighted Citation Impact
- 0.00