Considerations for Subgroup Analyses in Cluster-Randomized Trials Based on Aggregated Individual-Level Predictors.

In research assessing the effect of an intervention or exposure, a key secondary objective often involves assessing differential effects of this intervention or exposure in subgroups of interest; this is often referred to as assessing effect modification or heterogeneity of treatment effects (HTE). Observed HTE can have important implications for policy, including intervention strategies (e.g., will some patients benefit more from intervention than others?) and prioritizing resources (e.g., to reduce observed health disparities). Analysis of HTE is well understood in studies where the independent unit is an individual. In contrast, in studies where the independent unit is a cluster (e.g., a hospital or school) and a cluster-level outcome is used in the analysis, it is less well understood how to proceed if the HTE analysis of interest involves an individual-level characteristic (e.g., self-reported race) that must be aggregated at the cluster level. Through simulations, we show that only individual-level models have power to detect HTE by individual-level variables; if outcomes must be defined at the cluster level, then there is often low power to detect HTE by the corresponding aggregated variables. We illustrate the challenges inherent to this type of analysis in a study assessing the effect of an intervention on increasing COVID-19 booster vaccination rates at long-term care centers.

Did Access to Ambulatory Care Moderate the Associations Between Visit Mode and Ancillary Services Utilization Across the COVID-19 Pandemic Period?

BACKGROUND/OBJECTIVE: In recent years, 2 circumstances changed provider-patient interactions in primary care: the substitution of virtual (eg, video) for in-person visits and the COVID-19 pandemic. We studied whether access to care might affect patient fulfillment of ancillary services orders for ambulatory diagnosis and management of incident neck or back pain (NBP) and incident urinary tract infection (UTI) for virtual versus in-person visits. METHODS: Data were extracted from the electronic health records of 3 Kaiser Permanente Regions to identify incident NBP and UTI visits from January 2016 through June 2021. Visit modes were classified as virtual (Internet-mediated synchronous chats, telephone visits, or video visits) or in-person. Periods were classified as prepandemic [before the beginning of the national emergency (April 2020)] or recovery (after June 2020). Percentages of patient fulfillment of ancillary services orders were measured for 5 service classes each for NBP and UTI. Differences in percentages of fulfillments were compared between modes within periods and between periods within the mode to assess the possible impact of 3 moderators: distance from residence to primary care clinic, high deductible health plan (HDHP) enrollment, and prior use of a mail-order pharmacy program. RESULTS: For diagnostic radiology, laboratory, and pharmacy services, percentages of fulfilled orders were generally >70-80%. Given an incident NBP or UTI visit, longer distance to the clinic and higher cost-sharing due to HDHP enrollment did not significantly suppress patients' fulfillment of ancillary services orders. Prior use of mail-order prescriptions significantly promoted medication order fulfillments on virtual NBP visits compared with in-person NBP visits in the prepandemic period (5.9% vs. 2.0%, P=0.01) and in the recovery period (5.2% vs. 1.6%, P=0.02). CONCLUSIONS: Distance to the clinic or HDHP enrollment had minimal impact on the fulfillment of diagnostic or prescribed medication services associated with incident NBP or UTI visits delivered virtually or in-person; however, prior use of mail-order pharmacy option promoted fulfillment of prescribed medication orders associated with NBP visits.

Comparative Costs of Management Strategies for Neonates With Symptomatic Tetralogy of Fallot.

BACKGROUND: Recent data have demonstrated that overall mortality and adverse events are not significantly different for primary repair (PR) and staged repair (SR) approaches to management of neonates with symptomatic tetralogy of Fallot (sTOF). Cost data can be used to compare the relative value (cost for similar outcomes) of these approaches and are a potentially more sensitive measure of morbidity. OBJECTIVES: This study sought to compare the economic costs associated with PR and SR in neonates with sTOF. METHODS: Data from a multicenter retrospective cohort study of neonates with sTOF were merged with administrative data to compare total costs and cost per day alive over the first 18 months of life in a propensity score-adjusted analysis. A secondary analysis evaluated differences in department-level costs. RESULTS: In total, 324 subjects from 6 centers from January 2011 to November 2017 were studied (40% PR). The 18-month cumulative mortality (P = 0.18), procedural complications (P = 0.10), hospital complications (P = 0.94), and reinterventions (P = 0.22) did not differ between PR and SR. Total 18-month costs for PR (median $179,494 [IQR: $121,760-$310,721]) were less than for SR (median: $222,799 [IQR: $167,581-$327,113]) (P < 0.001). Cost per day alive (P = 0.005) and department-level costs were also all lower for PR. In propensity score-adjusted analyses, PR was associated with lower total cost (cost ratio: 0.73; P < 0.001) and lower department-level costs. CONCLUSIONS: In this multicenter study of neonates with sTOF, PR was associated with lower costs. Given similar overall mortality between treatment strategies, this finding suggests that PR provides superior value.

Noninvasive optical assessment of resting-state cerebral blood flow in children with sickle cell disease.

Sickle cell disease (SCD) is a genetic blood disorder that has profound effects on the brain. Chronic anemia combined with both macro- and microvascular perfusion abnormalities that arise from stenosis or occlusion of blood vessels increased blood viscosity, adherence of red blood cells to the vascular endothelium, and impaired autoregulatory mechanisms in SCD patients all culminate in susceptibility to cerebral infarction. Indeed, the risk of stroke is 250 times higher in children with SCD than in the general population. Unfortunately, while transcranial Doppler ultrasound (TCD) has been widely clinically adopted to longitudinally monitor macrovascular perfusion in these patients, routine clinical screening of microvascular perfusion abnormalities is challenging with current modalities (e.g., positron emission tomography and magnetic resonance imaging) given their high-cost, requirement for sedation in children < 6 year, and need for trained personnel. We assess the feasibility of a low-cost, noninvasive optical technique known as diffuse correlation spectroscopy (DCS) to quantify an index of resting-state cortical cerebral blood flow (BFI) in 11 children with SCD along with 11 sex- and age-matched healthy controls. As expected, BFI was significantly higher in SCD subjects compared to healthy controls ( p < 0.001 ). Within SCD subjects, BFI was inversely proportional to resting-state arterial hemoglobin levels ( p = 0.012 ), consistent with expected anemia-induced compensatory vasodilation that aims to maintain adequate oxygen delivery to the tissue. Further, in a subset of patients measured with TCD ( n = 7 ), DCS-measured blood flow was correlated with TCD-measured blood flow velocity in middle cerebral artery ( R s = 0.68 ), although the trend was not statistically significant ( p = 0.11 ). These results are consistent with those of several previous studies using traditional neuroimaging techniques, suggesting that DCS may be a promising low-cost tool for assessment of tissue-level CBF in pediatric SCD.

Differences in Cost of Care by Palliation Strategy for Infants With Ductal-Dependent Pulmonary Blood Flow.

BACKGROUND: In infants with ductal-dependent pulmonary blood flow, initial palliation with patent ductus arteriosus (PDA) stent or modified Blalock-Taussig (BT) shunt have comparable mortality but discrepant length of stay, procedural complication rates and reintervention burdens, which may influence cost. The relative economic impact of these palliation strategies is unknown. METHODS AND RESULTS: Retrospective study of infants with ductal-dependent pulmonary blood flow palliated with PDA stent (n=104) or BT shunt (n=251) from 2008 to 2015 at 4 centers of the Congenital Catheterization Research Collaborative. Inflation-adjusted inpatient hospital costs were calculated for first year of life using Pediatric Health Information System data. Costs derived from outpatient catheterizations not in Pediatric Health Information System were imputed. Costs were compared using propensity score-adjusted multivariable models, to account for baseline differences between groups. After propensity score adjustment, first year of life costs were significantly lower in PDA stent ($215 825 [190 644-244 333]) than BT shunt ($249 855 [230 693-270 609]) patients ( P=0.05). After addition of imputed costs, first year of life costs were not significantly different between PDA stent ($226 403 [200 274-255 941]) and BT shunt ($252 072 [232 955-272 759]) groups ( P=0.15). Patient characteristics associated with higher costs included: younger gestational age, genetic syndrome, noncardiac diagnoses, procedural complications, extracorporeal membrane oxygenation, duration of ventilation, intensive care unit and hospital length of stay and reintervention ( P≤0.02 for all). CONCLUSIONS: In this first multicenter comparative cost study of PDA stent or BT shunt as palliation for infants with ductal-dependent pulmonary blood flow, adjusted for baseline differences, PDA stent was associated with lower to equivalent costs over the first year of life. Combined with previous evidence suggesting clinical noninferiority, these findings suggest that PDA stent provides competitive health care value.

Racial disparities in presentation and outcomes of paediatric autoimmune hepatitis.

BACKGROUND & AIMS: Most studies on autoimmune hepatitis (AIH) in children are in predominantly Caucasian cohorts. Paediatric AIH in African Americans (AA) is understudied, with a dearth of clinical predictors of outcome, often leading to serious complications and even mortality. The aim of the study was to define disease presentation, progression, response to therapy and outcomes in paediatric AIH in a well-defined, large, single centre, demographically diverse population. METHODS: We conducted a review of patients with AIH who were followed at this tertiary liver transplant centre. Clinical and laboratory covariates were assessed with regard to disease presentation, progression and outcomes in AA vs Non-AA children. RESULTS: African Americans patients constituted 42% of this cohort. At 1-year follow-up, AA children were receiving significantly higher doses of steroids compared to non-AA. More AA presented with end-stage liver disease (ESLD) with high immunoglobulin G and GGT:platelet ratio. After adjusting for other risk factor variables like gender, age at presentation and ESLD, AA children were at 4.5 times higher risk for significant outcome liver transplant/death within the first 12 months of presentation. Post-transplant, recurrent AIH was seen in 50% of AA vs 8% in non-AA. CONCLUSIONS: African American patients with AIH are more likely to present with ESLD and have an increased early risk for transplantation with high likelihood of disease recurrence post-transplantation. Studies are needed to delineate factors such as inherent biology, genetics and access to care. Early referral and tailored immunosuppressive regimens are required for AA patients with AIH.

The Influence of Infectious Complications in Gastroschisis on Costs and Length of Stay.

Objective Outcomes for gastroschisis (GS) remain highly variable and avoiding infectious complications (ICs) may represent a significant improvement opportunity. Our objective was to provide estimates of the impact of IC on length of stay (LOS) and costs. Study Design Using a national database, 1,378 patients with GS were identified. Patient and hospital characteristics were compared and LOS and costs evaluated for patients with and without IC. Results Two-thirds of all GS patients had IC, and IC were common for simple and complex GS (65, 73%, respectively). After controlling for patient and hospital factors, LOS in patients with IC was significantly longer than in patients without IC (4.5-day increase, p = 0.001). Specifically, sepsis was associated with increasing median LOS by 11 days (p ≤ 0.001), candida infection by 14 days (p < 0.001), and wound infection by 7 days (p = 0.007). Although overall costs did not differ between patients with and without IC, costs were elevated based on specific IC. Sepsis increased median costs by $22,380 (95% confidence interval [CI]: $14,372-30,388; p ≤ 0.001), wound infection by $32,351 (95% CI: $17,221-47,481; p ≤ 0.001), catheter-related infection by $57,180 (95% CI: $12,834-101,527; p = 0.011), and candida infections by $24,500 (95% CI: $8,832-40,167; p = 0.002). Conclusion IC among GS patients are common and contribute to increased LOS and costs. Quantifying clinical and financial ramifications of IC may help direct future quality improvement efforts.

Syncope Best Practices: A Syncope Clinical Practice Guideline to Improve Quality.

OBJECTIVE: To determine whether implementation of a standardized clinical practice guideline (CPG) for the evaluation of syncope would decrease practice variability and resource utilization. DESIGN: A retrospective review of medical records of patients presenting to our practice for outpatient evaluation of syncope before and after implementation of the CPG. The guideline included elements of history, physical exam, electrocardiogram, and "red flags" for further testing. SETTING: Outpatient pediatric cardiology offices of a large pediatric cardiology practice. PATIENTS: All new patients between 3 and 21 years old, who presented to cardiology clinic with a chief complaint of syncope. INTERVENTIONS: The CPG for the evaluation of pediatric syncope was presented to the providers. OUTCOME MEASURES: Resource utilization was determined by the tests ordered by individual physicians before and after initiation of the CPG. Patient final diagnoses were recorded and the medical records were subsequently reviewed to determine if any patients, who presented again to the system, were ultimately diagnosed with cardiac disease. RESULTS: Of the 1496 patients with an initial visit for syncope, there was no significant difference in the diagnosis of cardiac disease before or after initiation of the CPG: (0.6% vs. 0.4%, P = .55). Electrocardiography provides the highest yield in the evaluation of pediatric syncope. Despite high compliance (86.9%), there were no overall changes in costs ($346.31 vs. $348.53, P = .85) or in resource utilization. There was, however, a decrease in the variability of ordering of echocardiograms among physicians, particularly among those at the extremes of utilization. CONCLUSIONS: Although the CPG did not decrease already low costs, it did decrease the wide variability in echo utilization. Evaluation beyond detailed history, physical exam, and electrocardiography provides no additional benefit in the evaluations of pediatric patients presenting with syncope.

Quantitative Assessment of Ventricular Septal Contour for Estimation of Right Ventricular Pressure.

BACKGROUND: Qualitative assessment of ventricular septal flattening is commonly used in pediatric patients with pulmonary hypertension (PH) who lack adequate tricuspid regurgitation (TR) Doppler signal. We sought to determine the relation between quantitative measures of septal flattening including the eccentricity index (EIs) and a novel marker, the septal flattening angle (SFA) with right ventricular systolic pressure (RVSP). METHODS: Subjects (≤18 years) with an anatomically normal heart, an adequate TR signal to obtain a peak velocity, and a simultaneous systemic systolic blood pressure (SBP) was included. RVSP was derived using TR gradient. Eccentricity index (EIs) and the SFA in systole were measured offline and correlated with RVSP/SBP. RESULTS: Of the 108 subjects, RVSP/SBP was < 50% in 77 and ≥ 50% in 31. In those with RVSP/SBP ≥50%, the median SFA was significantly lower (7.4° vs. 22°, p < 0.0001), and the median EIs was higher (1.61 vs. 1.07, p < 0.0001). SFA and EIs had a significant correlation with RVSP/SBP (rs = -0.70 and 0.61, respectively). Area under the curve was higher for SFA compared to EIs (0.92 and 0.85, respectively). The sensitivity and specificity of SFA for predicting an RVSP/SBP ≥ 50% using a cut point of 16° was 84% and 95% and for an EIs cut point of 1.35 was 74.2% and 96.1%, respectively. CONCLUSION: Septal flattening angle and EIs are quantitative measures of ventricular septal flattening that correlate well with RVSP/SBP and should be considered more routinely in clinical practice, especially in patients with inadequate TR Doppler signal.