Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Gaps in the Identification of Child Race and Ethnicity in a Pediatric Emergency Department

Introduction: Race and ethnicity are social constructs that are associated with meaningful health inequities. To address health disparities, it is essential to have valid, reliable race and ethnicity data. We compared child race and ethnicity as identified by the parent with that reported in the electronic health record (EHR).Methods: A convenience sample of parents of pediatric emergency department (PED) patients completed a tablet-based questionnaire (February-May 2021). Parents identified their child’s race and ethnicity from options within a single category. We used chi-square to compare concordance between child race and ethnicity reported by the parent with that recorded in the EHR.Results: Of 219 approached parents, 206 (94%) completed questionnaires. Race and/or ethnicity were misidentified in the EHR for 56 children (27%). Misidentifications were most common among children whose parents identified them as multiracial (100% vs 15% of children identified as a single race, P < 0.001) or Hispanic (84% vs 17% of non-Hispanic children, P < 0.001), and children whose race and/or ethnicity differed from that of their parent (79% vs 18% of children with the same race and ethnicity as their parent, P < 0.001).Conclusion: In this PED, misidentification of race and ethnicity was common. This study provides the basis for a multifaceted quality improvement effort at our institution. The quality of child race and ethnicity data in the emergency setting warrants further consideration across health equity efforts

Analysis of Racial and Ethnic Diversity of Population Served and Imaging Used in US Children\u27s Hospital Emergency Departments

Importance: Lower rates of diagnostic imaging have been observed among Black children compared with White children in pediatric emergency departments. Although the racial composition of the pediatric population served by each hospital differs, it is unclear whether this is associated with overall imaging rates at the hospital level, and in particular how it may be associated with the difference in imaging rates between Black and White children at a given hospital. Objective: To examine the association between the diversity of the pediatric population seen at each pediatric ED and variation in diagnostic imaging. Design, Setting, and Participants: Cross-sectional analysis of ED visits by patients younger than 18 years at 38 children\u27s hospitals from January 1, 2016, through December 31, 2019, using data from the Pediatric Health Information System. Data were analyzed from April to September 2021. Exposures: Proportion of patients from minoritized groups cared for at each hospital. Main Outcomes and Measures: The primary outcome was receipt of an imaging test defined as radiography, ultrasonography, computed tomography, or magnetic resonance imaging; adjusted odds ratios (aORs) were calculated to measure differences in imaging by race and ethnicity by hospital, and the correlation between the proportion of patients from minoritized groups cared for at each hospital and the aOR for receipt of diagnostic imaging by race and ethnicity was examined. Results: There were 12 310 344 ED visits (3 477 674 [28.3%] among Hispanic patients; 3 212 915 [26.1%] among non-Hispanic Black patients; 4 415 747 [35.9%] among non-Hispanic White patients; 6 487 660 [52.7%] among female patients) by 5 883 664 pediatric patients (mean [SD] age, 5.84 [5.23] years) to the 38 hospitals during the study period, of which 3 527 866 visits (28.7%) involved at least 1 diagnostic imaging test. Diagnostic imaging was performed in 1 508 382 visits (34.2%) for non-Hispanic White children, 790 961 (24.6%) for non-Hispanic Black children, and 907 222 (26.1%) for Hispanic children (P \u3c .001). Non-Hispanic Black patients were consistently less likely to receive diagnostic imaging than non-Hispanic White patients at each hospital, and for all imaging modalities. There was a significant correlation between the proportion of patients from minoritized groups cared for at the hospital and greater imaging difference between non-Hispanic White and non-Hispanic Black patients (correlation coefficient, -0.37; 95% CI, -0.62 to -0.07; P = .02). Conclusions and Relevance: In this cross-sectional study, hospitals with a higher percentage of pediatric patients from minoritized groups had larger differences in imaging between non-Hispanic Black and non-Hispanic White patients, with non-Hispanic White patients consistently more likely to receive diagnostic imaging. These findings emphasize the urgent need for interventions at the hospital level to improve equity in imaging in pediatric emergency medicine

Racial and Ethnic Differences in Insurer Classification of Nonemergent Pediatric Emergency Department Visits

IMPORTANCE: Government and commercial health insurers have recently enacted policies to discourage nonemergent emergency department (ED) visits by reducing or denying claims for such visits using retrospective claims algorithms. Low-income Black and Hispanic pediatric patients often experience worse access to primary care services necessary for preventing some ED visits, raising concerns about the uneven impact of these policies. OBJECTIVE: To estimate potential racial and ethnic disparities in outcomes of Medicaid policies for reducing ED professional reimbursement based on a retrospective diagnosis-based claims algorithm. DESIGN, SETTING, AND PARTICIPANTS: This simulation study used a retrospective cohort of pediatric ED visits (aged 0-18 years) for Medicaid-insured children and adolescents appearing in the Market Scan Medicaid database between January 1, 2016, and December 31, 2019. Visits missing date of birth, race and ethnicity, professional claims data, and Current Procedural Terminology codes of billing level of complexity were excluded, as were visits that result in admission. Data were analyzed from October 2021 to June 2022. MAIN OUTCOMES AND MEASURES: Proportion of ED visits algorithmically classified as nonemergent and simulated per-visit professional reimbursement after applying a current reimbursement reduction policy for potentially nonemergent ED visits. Rates were calculated overall and compared by race and ethnicity. RESULTS: The sample included 8 471 386 unique ED visits (43.0% by patients aged 4-12 years; 39.6% Black, 7.7% Hispanic, and 48.7% White), of which 47.7% were algorithmically identified as potentially nonemergent and subject to reimbursement reduction, resulting in a 37% reduction in ED professional reimbursement across the study cohort. More visits by Black (50.3%) and Hispanic (49.0%) children were algorithmically identified as nonemergent when compared with visits by White children (45.3%; P \u3c .001). Modeling the impact of the reimbursement reductions across the cohort resulted in expected per-visit reimbursement that was 6% lower for visits by Black children and 3% lower for visits by Hispanic children relative to visits by White children. CONCLUSIONS AND RELEVANCE: In this simulation study of over 8 million unique ED visits, algorithmic approaches for classifying pediatric ED visits that used diagnosis codes identified proportionately more visits by Black and Hispanic children as nonemergent. Insurers applying financial adjustments based on these algorithmic outputs risk creating uneven reimbursement policies across racial and ethnic groups

Variability in firearm injury among major pediatric trauma centers across the USA.

ObjectivesIn 2020, firearm injuries surpassed automobile collisions as the leading cause of death in US children. Annual automobile fatalities have decreased during 40 years through a multipronged approach. To develop similarly targeted public health interventions to reduce firearm fatalities, there is a critical need to first characterize firearm injuries and their outcomes at a granular level. We sought to compare firearm injuries, outcomes, and types of shooters at trauma centers in four pediatric health systems across the USA.MethodsWe retrospectively extracted data from each institution's trauma registry, paper and electronic health records. Study included all patients less than 19 years of age with a firearm injury between 2003 and 2018. Variables collected included demographics, intent, resources used, and emergency department and hospital disposition. Descriptive statistics were reported using medians and IQRs for continuous data and counts with percentages for categorical data. χ2 test or Fisher's exact test was conducted for categorical comparisons.ResultsOur cohort (n=1008, median age 14 years) was predominantly black and male. During the study period, there was an overall increase in firearm injuries, driven primarily by increases in the South (S) site (β=0.11 (SE 0.02), p=<0.001) in the setting of stable rates in the West and decreasing rates in the Northeast and Mid-Atlantic sites (β=-0.15 (SE 0.04), p=0.002; β=-0.19 (SE0.04), p=0.001). Child age, race, insurance type, resource use, injury type, and shooter type all varied by regional site.ConclusionThe incidence of firearm-related injuries seen at four sites during 15 years varied by site and region. The overall increase in firearm injuries was predominantly driven by the S site, where injuries were more often unintentional. This highlights the need for region-specific data to allow for the development of targeted interventions to impact the burden of injury.Level of Evidence: II, retrospective study

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types