Although the number of randomized controlled trials (RCTs) published each year involving adult populations is steadily rising, the annual number of RCTs published involving pediatric populations has not changed since 2005. Barriers to the broader utilization of RCTs in pediatrics include a lower prevalence of disease, less available funding, and more complicated regulatory requirements. Although child health researchers have been successful in overcoming these barriers for isolated diseases such as pediatric cancer, common pediatric diseases are underrepresented in RCTs relative to their burden. This article proposes a strategy called High-Efficiency RandOmIzed Controlled (HEROIC) trials to increase RCTs focused on common diseases among hospitalized children. HEROIC trials are multicenter RCTs that pursue the rapid, low-cost accumulation of study participants with minimal burden for individual sites. Five key strategies distinguish HEROIC trials: (1) dispersed low-volume recruitment, in which a large number of sites (50-150 hospitals) enroll a small number of participants per site (2-10 participants per site), (2) incentivizing site leads with authorship, training, education credits, and modest financial support, (3) a focus on pragmatic questions that examine simple, widely used interventions, (4) the use of a single institutional review board, integrated consent, and other efficient solutions to regulatory requirements, and (5) scaling the HEROIC trial strategy to accomplish multiple trials simultaneously. HEROIC trials can boost RCT feasibility and volume to answer fundamental clinical questions and improve care for hospitalized children.

<p><strong>Importance: </strong>Identifying high priority pediatric conditions is important for setting a research agenda in hospital pediatrics that will benefit families, clinicians, and the health care system. However, the last such prioritization study was conducted more than a decade ago and used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes.</p>

<p><strong>Objectives: </strong>To identify conditions that should be prioritized for comparative effectiveness research based on prevalence, cost, and variation in cost of hospitalizations using contemporary data at US children's hospitals.</p>

<p><strong>Design, Setting, and Participants: </strong>This retrospective cohort study of children with hospital encounters used data from the Pediatric Health Information System database. Children younger than 18 years with inpatient hospital encounters at 45 tertiary care US children's hospitals between January 1, 2016, and December 31, 2019, were included. Data were analyzed from March 2020 to April 2021.</p>

<p><strong>Main Outcomes and Measures: </strong>The condition-specific prevalence and total standardized cost, the corresponding prevalence and cost ranks, and the variation in standardized cost per encounter across hospitals were analyzed. The variation in cost was assessed using the number of outlier hospitals and intraclass correlation coefficient.</p>

<p><strong>Results: </strong>There were 2 882 490 inpatient hospital encounters (median [interquartile range] age, 4 [1-12] years; 1 554 024 [53.9%] boys) included. Among the 50 most prevalent and 50 most costly conditions (total, 74 conditions), 49 (66.2%) were medical, 15 (20.3%) were surgical, and 10 (13.5%) were medical/surgical. The top 10 conditions by cost accounted for $12.4 billion of $33.4 billion total costs (37.4%) and 592 815 encounters (33.8% of all encounters). Of 74 conditions, 4 conditions had an intraclass correlation coefficient (ICC) of 0.30 or higher (ie, major depressive disorder: ICC, 0.49; type 1 diabetes with complications: ICC, 0.36; diabetic ketoacidosis: ICC, 0.33; acute appendicitis without peritonitis: ICC, 0.30), and 9 conditions had an ICC higher than 0.20 (scoliosis: ICC, 0.27; hypertrophy of tonsils and adenoids: ICC, 0.26; supracondylar fracture of humerus: ICC, 0.25; cleft lip and palate: ICC, 0.24; acute appendicitis with peritonitis: ICC, 0.21). Examples of conditions high in prevalence, cost, and variation in cost included major depressive disorder (cost rank, 19; prevalence rank, 10; ICC, 0.49), scoliosis (cost rank, 6; prevalence rank, 38; ICC, 0.27), acute appendicitis with peritonitis (cost rank, 13; prevalence rank, 11; ICC, 0.21), asthma (cost rank, 10; prevalence rank, 2; ICC, 0.17), and dehydration (cost rank, 24; prevalence rank, 8; ICC, 0.18).</p>

<p><strong>Conclusions and Relevance: </strong>This cohort study found that major depressive disorder, scoliosis, acute appendicitis with peritonitis, asthma, and dehydration were high in prevalence, costs, and variation in cost. These results could help identify where future comparative effectiveness research in hospital pediatrics should be targeted to improve the care and outcomes of hospitalized children.</p>