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Review
. 2024 Sep 1;52(9):1439-1450.
doi: 10.1097/CCM.0000000000006371. Epub 2024 Aug 15.

Toward Precision in Critical Care Research: Methods for Observational and Interventional Studies

Emma J Graham Linck  1 , Ewan C Goligher  2   3   4 , Matthew W Semler  5   6 , Matthew M Churpek  1   7
Affiliations
Review

Toward Precision in Critical Care Research: Methods for Observational and Interventional Studies

Emma J Graham Linck et al. Crit Care Med. .

Abstract

Critical care trials evaluate the effect of interventions in patients with diverse personal histories and causes of illness, often under the umbrella of heterogeneous clinical syndromes, such as sepsis or acute respiratory distress syndrome. Given this variation, it is reasonable to expect that the effect of treatment on outcomes may differ for individuals with variable characteristics. However, in randomized controlled trials, efficacy is typically assessed by the average treatment effect (ATE), which quantifies the average effect of the intervention on the outcome in the study population. Importantly, the ATE may hide variations of the treatment's effect on a clinical outcome across levels of patient characteristics, which may erroneously lead to the conclusion that an intervention does not work overall when it may in fact benefit certain patients. In this review, we describe methodological approaches for assessing heterogeneity of treatment effect (HTE), including expert-derived subgrouping, data-driven subgrouping, baseline risk modeling, treatment effect modeling, and individual treatment rule estimation. Next, we outline how insights from HTE analyses can be incorporated into the design of clinical trials. Finally, we propose a research agenda for advancing the field and bringing HTE approaches to the bedside.

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Conflict of interest statement

Dr. Graham Linck was supported, in part, by the National Institutes of Health (NIH)/the National Library of Medicine (NLM) training grant (T15LM007359). Dr. Goligher is supported by grants from the Canadian Institutes of Health Research and the National Sanitarium Association; he received consulting fees from Lungpacer Medical, Stimit LLC, and Bioage; honoraria for lectures from Vyaire, Draeger, and Getinge; advisory board participation for Getinge (current) and Lungpacer (previous); and receipt of equipment for research from Timpel and Lungpacer. Dr. Semler was supported, in part, by a grant from the NIH/National Center for Advancing Translational Sciences (5UL1TR002243), a grant from the NIH/National Heart, Lung, and Blood Institute (NHLBI) (K23HL143053), and a grant from the U.S. Department of Defense. Dr. Semler reports having received compensation from Baxter Healthcare Corporation for having delivered two virtual lectures at conferences; an honorarium from the University of Pittsburgh; compensation from Baxter Healthcare Corporation for having served on a medical advisory board; compensation for continuing medical education lectures from Northwest Anesthesia Seminars; and an honorarium from the Cleveland Clinic. Dr. Churpek was supported by a grant from NIH/NHLBI (R01HL157262) and NLM; he is a named inventor on a patent (No. 11,410,777) for electronic Cardiac Arrest Risk Triage score, a risk stratification tool for ward patients, and receives royalties from this IP from the University of Chicago. Dr. Semler has disclosed that he does not have any potential conflicts of interest.

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