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Center for Clinical Trials Innovation (CCTI)

An international research, training, and collaboration hub that will improve health through methodological advances in clinical trials.

Publications

Explore more than a decade of impactful publications showcasing research led by Dr. Harhay, CCTI researchers, staff, and affiliated colleagues.

2025

Haines KJ, Leggett N, Hibbert E, Ali Abdelhamid Y, Bates S, Berney S, et al; icuRESOLVE-D Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. ICURESOLVE-D (Intensive Care Unit REcovery Solutions cO-Led through surVivor Engagement-Digital): Protocol for a multicentre randomised controlled trial of digital peer support for adult survivors of critical illness. Aust Crit Care. 2025 Aug 14;38(6):101303. doi:10.1016/j.aucc.2025.101303. Online ahead of print. PMID: 40815925.

Shannon MM, Keim G, Harhay MO, Yehya N. Parent and provider perspectives on short-term outcomes of critically ill ventilated children. Pediatr Crit Care Med. 2025 Sep 1;26(9):e1149-e1153. doi:10.1097/PCC.0000000000003794. Epub 2025 Jul 22. PMID: 40693858.

Zampieri FG, Cahusac PMB, Maia IS, Yehya N, Meyer NJ, Li F, Harhay MO. Trial analysis and interpretation in critical care using the evidential (likelihood) approach: rationale and practical considerations. Am J Respir Crit Care Med. 2025 Sep;211(9):1610-1621. doi:10.1164/rccm.202504-0809TR. PMID: 40591921.

Agarwal AK, Ebert JP, Xiong R, Ali ZS, Lee D, Shofer F, et al. Peer and patient feedback to increase adherence to postoperative opioid prescribing guidelines: a stepped-wedge cluster randomized clinical trial. JAMA Surg. 2025 Aug 1;160(8):866-874. doi:10.1001/jamasurg.2025.1672. PMID: 40498501. Clinical Trial.

Munroe ES, Spicer A, Castellvi-Font A, Zalucky A, Dianti J, Graham Linck E, et al; Platform of Randomized Adaptive Clinical Trials in Critical Illness (PRACTICAL) investigators; Evidence-based Individualized Treatment Effects (EvITE) Group. Evidence-based personalised medicine in critical care: a framework for quantifying and applying individualised treatment effects in patients who are critically ill. Lancet Respir Med. 2025 Jun;13(6):556-568. doi:10.1016/S2213-2600(25)00054-2. Epub 2025 Apr 15. PMID: 40250459.

de Grooth HJ, Yehya N, Harhay MO. Credible subgroup effects in randomized clinical trials. Am J Respir Crit Care Med. 2025 Jun;211(6):893-895. doi:10.1164/rccm.202502-0411ED. PMID: 40173213.

Courtright KR, Singh J, Dress EM, Bayes B, Harhay MO, Chowdhury M, et al. Nudging clinicians to promote serious illness communication for critically ill patients: a pragmatic cluster randomized trial. JAMA Intern Med. 2025 May 1;185(5):510-520. doi:10.1001/jamainternmed.2025.0090. PMID: 40094649.

Gasparini A, Crowther MJ, Hoogendijk EO, Li F, Harhay MO. Analysis of cohort stepped wedge cluster-randomized trials with nonignorable dropout via joint modeling. Stat Med. 2025 Feb 28;44(5):e10347. doi:10.1002/sim.10347. PMID: 39963907.

Isenberg D, Harhay MO, Mitra N, Li F. Weighting methods for truncation by death in cluster-randomized trials. Stat Methods Med Res. 2025 Mar;34(3):473-489. doi:10.1177/09622802241309348. Epub 2025 Jan 31. PMID: 39885759.

Bahti M, Kahan BC, Li F, Harhay MO, Auriemma CL. Prioritizing attributes of approaches to analyzing patient-centered outcomes that are truncated due to death in critical care clinical trials: a Delphi study. Trials. 2025 Jan 10;26(1):15. doi:10.1186/s13063-024-08673-x. PMID: 39794867.

Angriman F, Momenzade N, Adhikari NKJ, Mouncey PR, Asfar P, Yarnell CJ, et al. Blood pressure targets for adults with vasodilatory shock: an individual patient data meta-analysis. NEJM Evid. 2025 Jan;4(1):EVIDoa2400359. doi:10.1056/EVIDoa2400359. Epub 2024 Nov 18. PMID: 39556565.

2024

Cantu E, Isenberg D, Marquis A, Alcudia A, Yusuf S, Saleh A, et al. A pilot study to capture provider perspectives on clinically relevant effects in thoracic transplant trials. Am J Respir Crit Care Med. 2025 Jun;211(6):1079-1082. doi:10.1164/rccm.202408-1535RL. PMID: 40106820.

Leggett N, Ali Abdelhamid Y, Bicknell E, Booth S, Carmody J, Deane AM, et al; icuRESOLVE (icu Recovery Solutions Codesigned through Survivor Engagement) investigators. Virtual peer support for ICU survivors is feasible and may improve outcomes for ICU survivors: results from the icuRESOLVE-D (icu Recovery Solutions Codesigned through Survivor Engagement – Digital) pilot randomized controlled trial. Am J Respir Crit Care Med. 2024 Nov 15;210(10):1273-1276. doi:10.1164/rccm.202404-0780RL. PMID: 39312183.

Chen Z, Harhay MO, Fan E, Granholm A, McAuley DF, Urner M, et al. Statistical power and performance of strategies to analyze composites of survival and duration of ventilation in clinical trials. Crit Care Explor. 2024 Sep 20;6(10):e1152. doi:10.1097/CCE.0000000000001152. eCollection 2024 Oct 1. PMID: 39302988.

Goligher EC, Heath A, Harhay MO. Bayesian statistics for clinical research. Lancet. 2024 Sep 14;404(10457):1067-1076. doi:10.1016/S0140-6736(24)01295-9. PMID: 39277290.

Kahan BC, Blette BS, Harhay MO, Halpern SD, Jairath V, Copas A, Li F. Demystifying estimands in cluster-randomised trials. Stat Methods Med Res. 2024 Jul;33(7):1211-1232. doi:10.1177/09622802241254197. Epub 2024 May 23. PMID: 38780480.

Hosseini R, Chen Z, Goligher E, Fan E, Ferguson ND, Harhay MO, et al. Designing a Bayesian adaptive clinical trial to evaluate novel mechanical ventilation strategies in acute respiratory failure using integrated nested Laplace approximations. Contemp Clin Trials. 2024 Jul;142:107560. doi:10.1016/j.cct.2024.107560. Epub 2024 May 10. PMID: 38735571.

Blette BS, Halpern SD, Li F, Harhay MO. Assessing treatment effect heterogeneity in the presence of missing effect modifier data in cluster-randomized trials. Stat Methods Med Res. 2024 May;33(5):909-927. doi:10.1177/09622802241242323. Epub 2024 Apr 3. PMID: 38567439.

Granholm A, Lange T, Harhay MO, Perner A, Møller MH, Kaas-Hansen BS. Effects of sceptical priors on the performance of adaptive clinical trials with binary outcomes. Pharm Stat. 2024 Sep-Oct;23(5):728-741. doi:10.1002/pst.2387. Epub 2024 Mar 29. PMID: 38553422.

Legrand M, Bagshaw SM, Bhatraju PK, Bihorac A, Caniglia E, Khanna AK, et al. Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials. Crit Care. 2024 Mar 21;28(1):92. doi:10.1186/s13054-024-04877-4. PMID: 38515121.

Chen X, Harhay MO, Tong G, Li F. A Bayesian machine learning approach for estimating heterogeneous survivor causal effects: applications to a critical care trial. Ann Appl Stat. 2024 Mar;18(1):350-374. doi:10.1214/23-aoas1792. Epub 2024 Jan 31. PMID: 38455841.

PRACTICAL, PANTHER, TRAITS, INCEPT, and REMAP-CAP investigators. The rise of adaptive platform trials in critical care. Am J Respir Crit Care Med. 2024 Mar 1;209(5):491-496. doi:10.1164/rccm.202401-0101CP. PMID: 38271622.

Courtright KR, Madden V, Bayes B, Chowdhury M, Whitman C, Small DS, et al. Default palliative care consultation for seriously ill hospitalized patients: a pragmatic cluster randomized trial. JAMA. 2024 Jan 16;331(3):224-232. doi:10.1001/jama.2023.25092. PMID: 38227032.

Tong G, Tong J, Jiang Y, Esserman D, Harhay MO, Warren JL. Hierarchical Bayesian modeling of heterogeneous outcome variance in cluster randomized trials. Clin Trials. 2024 Aug;21(4):451-460. doi:10.1177/17407745231222018. Epub 2024 Jan 10. PMID: 38197388.

Wang W, Tong G, Hirani SP, Newman SP, Halpern SD, Small DS, et al. A mixed model approach to estimate the survivor average causal effect in cluster-randomized trials. Stat Med. 2024 Jan 15;43(1):16-33. doi:10.1002/sim.9939. Epub 2023 Nov 20. PMID: 37985966.

Goligher EC, Harhay MO. What is the point of Bayesian analysis? Am J Respir Crit Care Med. 2024 Mar 1;209(5):485-487. doi:10.1164/rccm.202310-1757VP. PMID: 37922491.

Granholm A, Lange T, Harhay MO, Jensen AKG, Perner A, Møller MH, et al. Effects of duration of follow-up and lag in data collection on the performance of adaptive clinical trials. Pharm Stat. 2024 Mar-Apr;23(2):138-150. doi:10.1002/pst.2342. Epub 2023 Oct 14. PMID: 37837271.

Brooks Carthon JM, Brom H, Amenyedor KE, Harhay MO, Grantham-Murillo M, Nikpour J, et al. Transitional care support for Medicaid-insured patients with serious mental illness: protocol for a Type I hybrid effectiveness-implementation stepped-wedge cluster randomized controlled trial. JMIR Res Protoc. 2024 Nov 12;13:e64575. doi:10.2196/64575. PMID: 39531274.

2023

Weatherald J, Moutchia J, Al-Naamani N, McClelland RL, Ventetuolo CE, Palevsky HI, et al. Win statistics in pulmonary arterial hypertension clinical trials. Am J Respir Crit Care Med. 2023 Dec 1;208(11):1231-1234. doi:10.1164/rccm.202305-0800LE. PMID: 37734029.

Kahan BC, Li F, Blette B, Jairath V, Copas A, Harhay M. Informative cluster size in cluster-randomised trials: a case study from the TRIGGER trial. Clin Trials. 2023 Dec;20(6):661-669. doi:10.1177/17407745231186094. Epub 2023 Jul 13. PMID: 37439089.

Granholm A, Kaas-Hansen BS, Lange T, Munch MW, Harhay MO, Zampieri FG, et al. Use of days alive without life support and similar count outcomes in randomised clinical trials: an overview and comparison of methodological choices and analysis methods. BMC Med Res Methodol. 2023 Jun 14;23(1):139. doi:10.1186/s12874-023-01963-z. PMID: 37316785.

Blette BS, Moutchia J, Al-Naamani N, Ventetuolo CE, Cheng C, Appleby D, et al. Is low-risk status a surrogate outcome in pulmonary arterial hypertension? An analysis of three randomised trials. Lancet Respir Med. 2023 Oct;11(10):873-882. doi:10.1016/S2213-2600(23)00155-8. Epub 2023 May 22. PMID: 37230098.

Blette BS, Granholm A, Li F, Shankar-Hari M, Lange T, Munch MW, et al. Causal Bayesian machine learning to assess treatment effect heterogeneity by dexamethasone dose for patients with COVID-19 and severe hypoxemia. Sci Rep. 2023 Apr 21;13(1):6570. doi:10.1038/s41598-023-33425-3. PMID: 37085591.

Zhu AY, Mitra N, Hemming K, Harhay MO, Li F. Leveraging baseline covariates to analyze small cluster-randomized trials with a rare binary outcome. Biom J. 2024 Jan;66(1):e2200135. doi:10.1002/bimj.202200135. Epub 2023 Apr 10. PMID: 37035941.

Tong J, Li F, Harhay MO, Tong G. Accounting for expected attrition in the planning of cluster randomized trials for assessing treatment effect heterogeneity. BMC Med Res Methodol. 2023 Apr 6;23(1):85. doi:10.1186/s12874-023-01887-8. PMID: 37024809.

Legrand M, Kothari R, Fong N, Palaniappa N, Boldt D, Chen LL, et al; VEGA-1 trial investigators. Norepinephrine versus phenylephrine for treating hypotension during general anaesthesia in adult patients undergoing major noncardiac surgery: a multicentre, open-label, cluster-randomised, crossover, feasibility, and pilot trial. Br J Anaesth. 2023 May;130(5):519-527. doi:10.1016/j.bja.2023.02.004. Epub 2023 Mar 14. PMID: 36925330.

Kahan BC, White IR, Edwards M, Harhay MO. Using modified intention-to-treat as a principal stratum estimator for failure to initiate treatment. Clin Trials. 2023 Jun;20(3):269-275. doi:10.1177/17407745231160074. Epub 2023 Mar 14. PMID: 36916466.

Tong G, Li F, Chen X, Hirani SP, Newman SP, Wang W, et al. A Bayesian approach for estimating the survivor average causal effect when outcomes are truncated by death in cluster-randomized trials. Am J Epidemiol. 2023 Jun 2;192(6):1006-1015. doi:10.1093/aje/kwad038. PMID: 36799630.

Friedrich JO, Harhay MO, Angus DC, Burns KEA, Cook DJ, Fergusson DA, et al; International Forum for Acute Care Trialists (InFACT). Mortality as a measure of treatment effect in clinical trials recruiting critically ill patients. Crit Care Med. 2023 Feb 1;51(2):222-230. doi:10.1097/CCM.0000000000005721. Epub 2023 Jan 20. PMID: 36661450.

Kahan BC, Li F, Copas AJ, Harhay MO. Estimands in cluster-randomized trials: choosing analyses that answer the right question. Int J Epidemiol. 2023 Feb 8;52(1):107-118. doi:10.1093/ije/dyac131. PMID: 35834775.

2022

Harhay MO, Blette BS, Granholm A, Moler FW, Zampieri FG, Goligher EC, et al. A Bayesian interpretation of a pediatric cardiac arrest trial (THAPCA-OH). NEJM Evid. 2023 Jan;2(1):EVIDoa2200196. doi:10.1056/EVIDoa2200196. Epub 2022 Dec 14. PMID: 38320098.

Patel B, Yver H, Woods-Hill CZ, Harhay MO, Yehya N. Elements of statistical power in pediatric critical care trials. Ann Am Thorac Soc. 2023 Jan;20(1):152-155. doi:10.1513/AnnalsATS.202202-154RL. PMID: 36044710.

Legrand M, Bagshaw SM, Koyner JL, Schulman IH, Mathis MR, Bernholz J, et al. Optimizing the design and analysis of future AKI trials. J Am Soc Nephrol. 2022 Aug;33(8):1459-1470. doi:10.1681/ASN.2021121605. Epub 2022 Jul 13. PMID: 35831022.

Casey JD, Beskow LM, Brown J, Brown SM, Gayat É, Ng Gong M, et al. Use of pragmatic and explanatory trial designs in acute care research: lessons from COVID-19. Lancet Respir Med. 2022 Jul;10(7):700-714. doi:10.1016/S2213-2600(22)00044-3. Epub 2022 Jun 13. PMID: 35709825.

Chen X, Harhay MO, Li F. Clustered restricted mean survival time regression. Biom J. 2023 Aug;65(6):e2200002. doi:10.1002/bimj.202200002. Epub 2022 May 20. PMID: 35593026.

2021

Krutsinger DC, Yadav KN, Harhay MO, Bartels K, Courtright KR. A systematic review and meta-analysis of enrollment into ARDS and sepsis trials published between 2009 and 2019 in major journals. Crit Care. 2021 Nov 15;25(1):392. doi:10.1186/s13054-021-03804-1. PMID: 34781998.

Wilkinson J, Huang JY, Marsden A, Harhay MO, Vail A, Roberts SA. The implications of outcome truncation in reproductive medicine RCTs: a simulation platform for trialists and simulation study. Trials. 2021 Aug 6;22(1):520. doi:10.1186/s13063-021-05482-4. PMID: 34362422.

Auriemma CL, Taylor SP, Harhay MO, Courtright KR, Halpern SD. Hospital-free days: a pragmatic and patient-centered outcome for trials among critically and seriously ill patients. Am J Respir Crit Care Med. 2021 Oct 15;204(8):902-909. doi:10.1164/rccm.202104-1063PP. PMID: 34319848.

Arrigo M, Price S, Baran DA, Pöss J, Aissaoui N, Bayes-Genis A, et al. Optimising clinical trials in acute myocardial infarction complicated by cardiogenic shock: a statement from the 2020 Critical Care Clinical Trialists Workshop. Lancet Respir Med. 2021 Oct;9(10):1192-1202. doi:10.1016/S2213-2600(21)00172-7. Epub 2021 Jul 7. PMID: 34245691.

Colantuoni E, Koneru M, Akhlaghi N, Li X, Hashem MD, Dinglas VD, et al. Heterogeneity in design and analysis of ICU delirium randomized trials: a systematic review. Trials. 2021 May 20;22(1):354. doi:10.1186/s13063-021-05299-1. PMID: 34016134.

Yehya N, Harhay MO. Severity of hypoxemia may explain indeterminate results in pediatric trials of inhaled nitric oxide. Intensive Care Med. 2021 Aug;47(8):913-915. doi:10.1007/s00134-021-06434-x. Epub 2021 May 16. PMID: 33993339.

Zampieri FG, Casey JD, Shankar-Hari M, Harrell FE Jr, Harhay MO. Using Bayesian methods to augment the interpretation of critical care trials: an overview of theory and example reanalysis of the alveolar recruitment for acute respiratory distress syndrome trial. Am J Respir Crit Care Med. 2021 Mar 1;203(5):543-552. doi:10.1164/rccm.202006-2381CP. PMID: 33270526.

2020

Kim J, Troxel AB, Halpern SD, Volpp KG, Kahan BC, Morris TP, et al. Analysis of multicenter clinical trials with very low event rates. Trials. 2020 Nov 9;21(1):917. doi:10.1186/s13063-020-04801-5. PMID: 33168073.

Harhay MO, Gasparini A, Walkey AJ, Weissman GE, Crowther MJ, Ratcliffe SJ, et al. Assessing the course of organ dysfunction using joint longitudinal and time-to-event modeling in the vasopressin and septic shock trial. Crit Care Explor. 2020 Apr 29;2(4):e0104. doi:10.1097/CCE.0000000000000104. eCollection 2020 Apr. PMID: 32426746.\

Harhay MO, Casey JD, Clement M, Collins SP, Gayat É, Gong MN, et al. Contemporary strategies to improve clinical trial design for critical care research: insights from the First Critical Care Clinical Trialists Workshop. Intensive Care Med. 2020 May;46(5):930-942. doi:10.1007/s00134-020-05934-6. Epub 2020 Feb 18. PMID: 32072303.

2019

Yehya N, Harhay MO, Curley MAQ, Schoenfeld DA, Reeder RW. Reappraisal of ventilator-free days in critical care research. Am J Respir Crit Care Med. 2019 Oct 1;200(7):828-836. doi:10.1164/rccm.201810-2050CP. PMID: 31034248.

Harhay MO, Ratcliffe SJ, Small DS, Suttner LH, Crowther MJ, Halpern SD. Measuring and analyzing length of stay in critical care trials. Med Care. 2019 Sep;57(9):e53-e59. doi:10.1097/MLR.0000000000001059. PMID: 30664613.

2017

Harhay MO, Ratcliffe SJ, Halpern SD. Measurement error due to patient flow in estimates of intensive care unit length of stay. Am J Epidemiol. 2017 Dec 15;186(12):1389-1395. doi:10.1093/aje/kwx222. PMID: 28605399.

2016

Kahan BC, Forbes G, Ali Y, Jairath V, Bremner S, Harhay MO, et al. Increased risk of type I errors in cluster randomised trials with small or medium numbers of clusters: a review, reanalysis, and simulation study. Trials. 2016 Sep 6;17(1):438. doi:10.1186/s13063-016-1571-2. PMID: 27600609.

Mebazaa A, Laterre PF, Russell JA, Bergmann A, Gattinoni L, Gayat E, et al. Designing phase 3 sepsis trials: application of learned experiences from critical care trials in acute heart failure. J Intensive Care. 2016 Mar 31;4:24. doi:10.1186/s40560-016-0151-6. eCollection 2016. PMID: 27034779.

Harhay MO, Russell JA. Designing better, not just bigger, multicenter critical care trials. Crit Care Med. 2016 Jan;44(1):e48-e49. doi:10.1097/CCM.0000000000001316. PMID: 26672939.

2015

Kahan BC, Harhay MO. Many multicenter trials had few events per center, requiring analysis via random-effects models or GEEs. J Clin Epidemiol. 2015 Dec;68(12):1504-1511. doi:10.1016/j.jclinepi.2015.03.016. Epub 2015 Apr 2. PMID: 25985892.

Halpern SD, French B, Small DS, Saulsgiver K, Harhay MO, Audrain-McGovern J, et al. Randomized trial of four financial-incentive programs for smoking cessation. N Engl J Med. 2015 May 28;372(22):2108-2117. doi:10.1056/NEJMoa1414293. Epub 2015 May 13. PMID: 25970009.

French B, Small DS, Novak J, Saulsgiver KA, Harhay MO, Asch DA, et al. Preference-adaptive randomization in comparative effectiveness studies. Trials. 2015 Mar 18;16:99. doi:10.1186/s13063-015-0592-6. PMID: 25887045.

2014

Harhay MO, Wagner J, Ratcliffe SJ, Bronheim RS, Gopal A, Green S, et al. Outcomes and statistical power in adult critical care randomized trials. Am J Respir Crit Care Med. 2014 Jun 15;189(12):1469-1478. doi:10.1164/rccm.201401-0056CP. PMID: 24786714.

2013

Kerlin MP, Small DS, Cooney E, Fuchs BD, Bellini LM, Mikkelsen ME, et al. A randomized trial of nighttime physician staffing in an intensive care unit. N Engl J Med. 2013 Jun 6;368(23):2201-2209. doi:10.1056/NEJMoa1302854. Epub 2013 May 20. PMID: 23688301.

Halpern SD, Loewenstein G, Volpp KG, Cooney E, Vranas K, Quill CM, et al. Default options in advance directives influence how patients set goals for end-of-life care. Health Aff (Millwood). 2013 Feb;32(2):408-417. doi:10.1377/hlthaff.2012.0895. PMID: 23381535.

2011

Pérez V, Saénz D, Madriz J, Harhay M, Feoli J, Castro M, et al. A double-blind study of the efficacy and safety of multiple daily doses of amikacin versus one daily dose for children with perforated appendicitis in Costa Rica. Int J Infect Dis. 2011 Aug;15(8):e569-e575. doi:10.1016/j.ijid.2011.04.012. Epub 2011 Jul 5. PMID: 21733727.