Comparing the Diagnostic Yield of Germline Exome Versus Panel Sequencing in the Diverse Population of the Texas KidsCanSeq Pediatric Cancer Study.

PURPOSE: To evaluate the relative diagnostic yield of clinical germline genomic tests in a diverse pediatric cancer population. PATIENTS AND METHODS: The KidsCanSeq study enrolled pediatric cancer patients across six sites in Texas. Germline analysis included both exome sequencing and a therapy-focused pediatric cancer gene panel. The results were categorized by participants demographics, the presence of pathogenic or likely pathogenic (P/LP) variants, and variants of uncertain significance (VUS) in cancer predisposition genes (CPGs). Pediatric actionable CPGs were defined as those with cancer surveillance recommendations during childhood. RESULTS: Cancer P/LP variants were reported by at least one platform in 103 of 578 (17.8%) participants of which 76 were dominant cancer genes (13.1%) with no significant differences by self-described race or Hispanic ethnicity. However, the proportion of participants with VUS was greater in Asian and African American participants (P = .0029). Diagnostic yield was 16.6% for exome versus 8.5% for panel (P < .0001) with 42 participants with concordant germline results. Exome-only results included P/LP variants in 30 different CPGs in 54 participants, whereas panel-only results included seven participants with a copy number or structural P/LP variants in CPGs. There was no significant difference in diagnostic yield limited to pediatric actionable CPGs (P = .6171). CONCLUSION: Approximately 18% of a diverse pediatric cancer population had germline diagnostic findings with 50% of P/LP variants reported by only one platform because of CPGs not on the targeted panel and copy number variants (CNVs)/rearrangements not reported by exome. Although diagnostic yields were similar in this diverse population, increases in VUS results were observed in Asian and African American populations. Given the clinical significance of CNVs/rearrangements in this cohort, detection is critical to optimize germline analysis of pediatric cancer populations.

Healthcare Spending and Systemic Bevacizumab for Recurrent Respiratory Papillomatosis.

OBJECTIVES: Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare, costly condition linked to human papillomavirus. Standard of care is serial surgical debridement. Many adjunctive therapies have been trialed, with recent success with systemic bevacizumab. This paper examines healthcare spending associated with systemic bevacizumab use for JoRRP and compares it to healthcare spending for surgical care alone to determine whether bevacizumab has a financial benefit. METHODS: Five patients treated with systemic bevacizumab for JoRRP were identified at a single institution. Spending data was derived from the electronic medical record. Sensitivity analysis was performed using variation in spending and frequency of treatments. RESULTS: Patients had an average of 4.2 treatments per year prior to bevacizumab (95% confidence interval [CI] 1.4-7.0) and 1.1 after (0.2-2.0). Patients underwent an average of 9.2 bevacizumab treatments in their first year after initiation, 4.0 in the second, and 4.5 in their third. Mean payment per debridement was $3198 ($2856-3539), with mean total surgical payment per year of $17,966 ($11,673-24,259) prior to initiating bevacizumab. Mean payment on a single bevacizumab infusion visit was $6508 ($6063-6952). Mean total surgical and bevacizumab spending per year after bevacizumab initiation were $83,951 ($12,938-154,964). CONCLUSIONS: Accounting for variations in the number of treatments per year with bevacizumab after initiation, healthcare spending after bevacizumab initiation is similar to spending on surgery alone for JoRRP in patients with severe disease.

Teaching and Safety-Net Hospital Penalization in the Hospital-Acquired Condition Reduction Program.

Importance: The Hospital-Acquired Condition Reduction Program (HACRP) evaluates acute care hospitals on the occurrence of patient safety events and health care-associated infections. Since its implementation, several studies have raised concerns about the overpenalization of teaching and safety-net hospitals, and although several changes in the program's methodology have been applied in the last few years, whether these changes reversed the overpenalization of teaching and safety-net hospitals is unknown. Objective: To determine hospital characteristics associated with HACRP penalization and penalization reversal. Design, Setting, and Participants: This retrospective cross-sectional study assessed data from 3117 acute care hospitals participating in the HACRP. The HACRP penalization and hospital characteristics were obtained from Hospital Compare (2020 and 2021), the Inpatient Prospective Payment System impact file (2020), and the American Hospital Association annual survey (2018). Exposures: Hospital characteristics, including safety-net status and teaching intensity (no teaching and very minor, minor, major, and very major teaching levels). Main Outcomes and Measures: The primary outcome was HACRP penalization (ie, hospitals that fell within the worst quartile of the program's performance). Multivariable models initially included all covariates, and then backward stepwise variable selection was used. Results: Of 3117 hospitals that participated in HACRP in 2020, 779 (25.0%) were safety-net hospitals and 1090 (35.0%) were teaching institutions. In total, 771 hospitals (24.7%) were penalized. The HACRP penalization was associated with safety-net status (odds ratio [OR], 1.41 [95% CI, 1.16-1.71]) and very major teaching intensity (OR, 1.94 [95% CI, 1.15-3.28]). In addition, non-federal government hospitals were more likely to be penalized than for-profit hospitals (OR, 1.62 [95% CI, 1.23-2.14]), as were level I trauma centers (OR, 2.05 [95% CI, 1.43-2.96]) and hospitals located in the New England region (OR, 1.65 [95% CI, 1.12-2.43]). Safety-net hospitals with major teaching levels were twice as likely to be penalized as non-safety-net nonteaching hospitals (OR, 2.15 [95% CI, 1.14-4.03]). Furthermore, safety-net hospitals penalized in 2020 were less likely (OR, 0.64 [95% CI, 0.43-0.96]) to revert their HACRP penalization status in 2021. Conclusions and Relevance: Findings from this cross-sectional study indicated that teaching and safety-net hospital status continued to be associated with overpenalization in the HACRP despite recent changes in its methodology. Most of these hospitals were also less likely to revert their penalization status. A reevaluation of the program methodology is needed to avoid depleting resources of hospitals caring for underserved populations.

Child Health and the Pediatric Hematology-Oncology Workforce: 2020-2040.

Pediatric hematology-oncology (PHO) is 1 of the oldest recognized pediatric subspecialities. PHO physicians care for infants, children, adolescents, and young adults with all types of cancer and nonmalignant blood conditions, in many cases temporarily assuming the role of a primary care physician because of the complexity and intensity of treatment. However, the number of clinically active PHO subspecialists needed to care for children in the United States remains unknown. Recent papers suggest a potential oversaturation of PHO physicians in some geographic areas. This article is part of a Pediatrics supplement focused on projecting the future supply of the pediatric subspecialty workforce. It draws on information available in the literature, data from the American Board of Pediatrics, and findings from a new microsimulation model estimating the future supply of pediatric subspecialists through 2040. The model predicts a workforce growth in PHO subspecialists of 66% by 2040. Alternative scenarios, including changes in clinical time and fellowship size, resulted in a difference in growth of ±18% from baseline. The model also forecasts significant geographic maldistribution. For example, the current workforce is concentrated in the Northeast Census region and the model predicts the New England Census division will have a 2.9-fold higher clinical workforce equivalent per 100 000 children aged 0 to 18 years than the Mountain Census division by 2040. These findings suggest potential opportunities to improve the PHO subspecialty workforce and the outcomes and experiences of its patient population through educational changes, practice initiatives, policy interventions, and dedicated research.

Price Increases Versus Upcoding As Drivers Of Emergency Department Spending Increases, 2012-19.

Recent studies document a substantial increase in emergency department (ED) spending in the past decade, even though the number of ED visits per capita has remained relatively stable. Price increases and upcoding are sometimes cited as possible explanations, but their relative impacts are not known. We analyzed Blue Cross Blue Shield claims for patients of all ages who received care in EDs in five states in 2012 and 2019. We used estimates from spending regressions and regressions explaining coding intensity to decompose changes in spending between 2012 and 2019 into components attributable to price increases, changes in patient characteristics or treatment intensity, and upcoding. Prices accounted for at least half of the increase in ED spending per visit for four of the five states we examined. Increases in spending attributable to upcoding were notable but generally not as large. Future research should explore the associations between local market conditions, such as consolidation and ownership type, and both price increases and upcoding.

Parent-Reported Clinical Utility of Pediatric Genomic Sequencing.

BACKGROUND AND OBJECTIVES: Genomic sequencing (GS) is increasingly used for diagnostic evaluation, yet follow-up care is not well understood. We assessed clinicians' recommendations after GS, parent-reported follow-up, and actions parents initiated in response to learning their child's GS results. METHODS: We surveyed parents of children who received GS through the Clinical Sequencing Evidence Generating Research consortium ∼5 to 7 months after return of results. We compared the proportion of parents who reported discussing their child's result with a clinician, clinicians' recommendations, and parents' follow-up actions by GS result type using χ2 tests. RESULTS: A total of 1188 respondents completed survey measures on recommended medical actions (n = 1187) and/or parent-initiated actions (n = 913). Most parents who completed recommended medical actions questions (n = 833, 70.3%) reported having discussed their child's GS results with clinicians. Clinicians made recommendations to change current care for patients with positive GS results (n = 79, 39.1%) more frequently than for those with inconclusive (n = 31, 12.4%) or negative results (n = 44, 11.9%; P < .001). Many parents discussed (n = 152 completed, n = 135 planned) implications of GS results for future pregnancies with a clinician. Aside from clinical recommendations, 13.0% (n = 119) of parents initiated changes to their child's health or lifestyle. CONCLUSIONS: In diverse pediatric clinical contexts, GS results can lead to recommendations for follow-up care, but they likely do not prompt large increases in the quantity of care received.

Conducting clinical genomics research during the COVID-19 pandemic: Lessons learned from the CSER consortium experience.

Clinical research studies have navigated many changes throughout the COVID-19 pandemic. We sought to describe the pandemic's impact on research operations in the context of a clinical genomics research consortium that aimed to enroll a majority of participants from underrepresented populations. We interviewed (July to November 2020) and surveyed (May to August 2021) representatives of six projects in the Clinical Sequencing Evidence-Generating Research (CSER) consortium, which studies the implementation of genome sequencing in the clinical care of patients from populations that are underrepresented in genomics research or are medically underserved. Questions focused on COVID's impact on participant recruitment, enrollment, and engagement, and the transition to teleresearch. Responses were combined and thematically analyzed. Projects described factors at the project, institutional, and community levels that affected their experiences. Project factors included the project's progress at the pandemic's onset, the urgency of in-person clinical care for the disease being studied, and the degree to which teleresearch procedures were already incorporated. Institutional and community factors included institutional guidance for research and clinical care and the burden of COVID on the local community. Overall, being responsive to community experiences and values was essential to how CSER navigated evolving challenges during the COVID-19 pandemic.

Lessons learned while starting multi-institutional genetics research in diverse populations: A report from the Clinical Sequencing Evidence-Generating Research (CSER) consortium.

BACKGROUND: Increasing diversity in clinical trial participation is necessary to improve health outcomes and requires addressing existing social, structural, and geographic barriers. The Clinical Sequencing Evidence-Generating Research Consortium (CSER) included six research projects to enroll historically underrepresented/underserved (UR/US) populations in clinical genomics research. Delays and project re-designs emerged shortly after work began. Understanding common experiences of these projects may inform future trial implementation. METHODS: Semi-structured interviews with six CSER principal investigators and seven project managers were performed. An interview guide included questions of research/clinical infrastructure, logistics across sites, language, communication, and allocation of grant-related resources. Interviews were recorded, transcribed verbatim; transcripts were analyzed using inductive coding, thematic analysis and consensus building. RESULTS: All projects collaborating with new clinical sub-sites to recruit UR/US populations. Refining trial logistics continued long after enrollment for all projects. Themes of challenges included: sub-site customization for workflow and genetics support, conflicting input from participant advisory groups and approval bodies, developing research personnel, complex data management structures, and external changes (e.g. subcontractors ending contracts) that required redesign. Themes of beneficial lessons included: domains with prior experience were easier, develop project champions at each sub-site, structure communication within the research team, and simplify research design when possible. CONCLUSIONS: The operational aspects of expanding clinical research into novel sub-sites are significant and require investment of time and resources. The themes arising from these interviews suggest priority areas for more quantitative analyses in the future including multi-institutional approval policies and processes, data management structures, and incremental research complexity.

Cost-effectiveness frameworks for comparing genome and exome sequencing versus conventional diagnostic pathways: A scoping review and recommended methods.

PURPOSE: Methodological challenges have limited economic evaluations of genome sequencing (GS) and exome sequencing (ES). Our objective was to develop conceptual frameworks for model-based cost-effectiveness analyses (CEAs) of diagnostic GS/ES. METHODS: We conducted a scoping review of economic analyses to develop and iterate with experts a set of conceptual CEA frameworks for GS/ES for prenatal testing, early diagnosis in pediatrics, diagnosis of delayed-onset disorders in pediatrics, genetic testing in cancer, screening of newborns, and general population screening. RESULTS: Reflecting on 57 studies meeting inclusion criteria, we recommend the following considerations for each clinical scenario. For prenatal testing, performing comparative analyses of costs of ES strategies and postpartum care, as well as genetic diagnoses and pregnancy outcomes. For early diagnosis in pediatrics, modeling quality-adjusted life years (QALYs) and costs over ≥20 years for rapid turnaround GS/ES. For hereditary cancer syndrome testing, modeling cumulative costs and QALYs for the individual tested and first/second/third-degree relatives. For tumor profiling, not restricting to treatment uptake or response and including QALYs and costs of downstream outcomes. For screening, modeling lifetime costs and QALYs and considering consequences of low penetrance and GS/ES reanalysis. CONCLUSION: Our frameworks can guide the design of model-based CEAs and ultimately foster robust evidence for the economic value of GS/ES.

Financial Implications of Short Stay Pediatric Hospitalizations.

BACKGROUND: Observation status (OBS) stays incur similar costs to low-acuity, short-stay inpatient (IP) hospitalizations. Despite this, payment for OBS is likely less and may represent a financial liability for children's hospitals. Thus, we described the financial outcomes associated with OBS stays compared to similar IP stays by hospital and payer. METHODS: We conducted a retrospective cohort study of clinically similar pediatric OBS and IP encounters at 15 hospitals contributing to the revenue management program in 2017. Clinical and demographic characteristics were described. For each hospitalization, the cost coverage ratio (CCR) was calculated by dividing revenue by estimated cost of hospitalization. Differences in CCR were evaluated using Wilcoxon rank sum tests and results were stratified by billing designation and payer. CCR for OBS and IP stays were compared by institution, and the estimated increase in revenue by billing OBS stays as IP was calculated. RESULTS: OBS was assigned to 70 981 (56.9%) of 124 789 hospitalizations. Use of OBS varied across hospitals (8%-86%). For included hospitalizations, OBS stays were more likely than IP stays to result in financial loss (57.0% vs 35.7%). OBS stays paid by public payer had the lowest median CCR (0.6; interquartile range [IQR], 0.2-0.9). Paying OBS stays at the median IP rates would have increased revenue by $167 million across the 15 hospitals. CONCLUSIONS: OBS stays were significantly more likely to result in poor financial outcomes than similar IP stays. Costs of hospitalization and billing designations are poorly aligned and represent an opportunity for children's hospitals and payers to restructure payment models.

Is Detection of Relapse by Surveillance Imaging Associated With Longer Survival in Patients With Rhabdomyosarcoma?

BACKGROUND: We investigated whether surveillance imaging had an impact on post-relapse survival in patients with rhabdomyosarcoma (RMS). We hypothesized that relapse detected by imaging (group IM) would be associated with longer survival compared with relapse detected with a clinical sign or symptom (group SS). MATERIALS AND METHODS: We performed an observational multi-institutional study in 127 patients with relapsed RMS comparing overall survival (OS) after relapse using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Relapse was detected in 60 (47%) group IM and 67 (53%) SS patients. Median follow-up in survivors was 4 years (range 1.0 to 16.7 y). Four-year OS rates were similar between group IM (28%, 95% confidence interval [CI]: 14%-40%) and SS (21%, 95% CI: 11%-31%) ( P =0.14). In multivariable analyses accounting for institution, age at diagnosis, time to relapse, risk group at diagnosis, and primary site, not receiving chemotherapy (hazard ratio [HR]: 6.8, 95% CI: 2.8-16.6), radiation (HR: 3, 95% CI: 1.7-5.3), or surgery (HR: 2.8, 95% CI: 1.6-4.8) after relapse were independently associated with poor OS. CONCLUSION: These results on whether surveillance imaging provides survival benefit in patients with relapsed RMS are inconclusive. Larger studies are needed to justify current surveillance recommendations. Chemotherapy, radiotherapy and surgery to treat recurrence prolong OS.

Rising drug cost impacts on cost-effectiveness of 2 chemotherapy regimens for intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group.

BACKGROUND: The Children's Oncology Group clinical trial for intermediate risk rhabdomyosarcoma randomized participants to a combination of vincristine, dactinomycin, and cyclophosphamide (VAC) alone or VAC alternating with vincristine plus irinotecan (VAC/VI). Clinical outcomes were similar, but toxicity profiles differed. This study estimates the cost differences between arms from the health care system's perspective. METHODS: A decision-analytic model was used to estimate the incremental cost-effectiveness ratio (ICER) of VAC versus VAC/VI. Protocol-required or recommended medications and laboratory studies were included. Costs were obtained from national databases or supporting literature and inflated to 2019 US dollars. Demographic and outcome data were obtained from the clinical trial and directed chart reviews. Life-years (LY) were estimated from life-expectancy tables and discounted by 3% annually. Probabilistic sensitivity analyses and alternative clinical scenarios identified factors driving costs. RESULTS: Mean direct medical costs of VAC and VAC/VI were $164,757 and $102,303, respectively. VAC was associated with an additional 0.97 LY and an ICER of $64,386/LY compared with VAC/VI. The ICER was sensitive to survival estimations and to alternative clinical scenarios including outpatient cyclophosphamide delivery (ICER $49,037/LY) or substitution of alternative hematopoietic growth factor schedules (ICER $73,191-$91,579/LY). Applying drug prices from 2012 decreased the total costs of VAC by 20% and VAC/VI by 15% because of changes in dactinomycin and pegfilgrastim prices. CONCLUSIONS: Neither arm was clearly more cost-effective. Pharmaceutical pricing and location of treatment drove costs and may inform future treatment decisions. Rising pharmaceutical costs added $30,000 per patient, a finding important for future drug-pricing policy decisions. LAY SUMMARY: Two chemotherapy regimens recently tested side-by-side for rhabdomyosarcoma had similar tumor outcomes, but different side effects. The health care costs of each regimen were compared; neither was clearly more cost-effective. However, the costs of each treatment changed dramatically with choices of supportive medicines and location of treatment. Costs of treatment rose by 15% to 20% because of rising US drug costs not associated with the clinical trial.

US private payers' perspectives on insurance coverage for genome sequencing versus exome sequencing: A study by the Clinical Sequencing Evidence-Generating Research Consortium (CSER).

PURPOSE: There is limited payer coverage for genome sequencing (GS) relative to exome sequencing (ES) in the U.S. Our objective was to assess payers' considerations for coverage of GS versus coverage of ES and requirements payers have for coverage of GS. The study was conducted by the NIH-funded Clinical Sequencing Evidence-Generating Research Consortium (CSER). METHODS: We conducted semi-structured interviews with representatives of private payer organizations (payers, N = 12) on considerations and evidentiary and other needs for coverage of GS and ES. Data were analyzed using thematic analysis. RESULTS: We described four categories of findings and solutions: demonstrated merits of GS versus ES, enhanced methods for evidence generation, consistent laboratory processes/sequencing methods, and enhanced implementation/care delivery. Payers see advantages to GS vs. ES and are open to broader GS coverage but need more proof of these advantages to consider them in coverage decision-making. Next steps include establishing evidence of benefits in specific clinical scenarios, developing quality standards, ensuring transparency of laboratory methods, developing clinical centers of excellence, and incorporating the role of genetic professionals. CONCLUSION: By comparing coverage considerations for GS and ES, we identified a path forward for coverage of GS. Future research should explicitly address payers' conditions for coverage.

A safety and feasibility trial of 131 I-MIBG in newly diagnosed high-risk neuroblastoma: A Children's Oncology Group study.

INTRODUCTION: 131 I-meta-iodobenzylguanidine (131 I-MIBG) is effective in relapsed neuroblastoma. The Children's Oncology Group (COG) conducted a pilot study (NCT01175356) to assess tolerability and feasibility of induction chemotherapy followed by 131 I- MIBG therapy and myeloablative busulfan/melphalan (Bu/Mel) in patients with newly diagnosed high-risk neuroblastoma. METHODS: Patients with MIBG-avid high-risk neuroblastoma were eligible. After the first two patients to receive protocol therapy developed severe sinusoidal obstruction syndrome (SOS), the trial was re-designed to include an 131 I-MIBG dose escalation (12, 15, and 18 mCi/kg), with a required 10-week gap before Bu/Mel administration. Patients who completed induction chemotherapy were evaluable for assessment of 131 I-MIBG feasibility; those who completed 131 I-MIBG therapy were evaluable for assessment of 131 I-MIBG + Bu/Mel feasibility. RESULTS: Fifty-nine of 68 patients (86.8%) who completed induction chemotherapy received 131 I-MIBG. Thirty-seven of 45 patients (82.2%) evaluable for 131 I-MIBG + Bu/Mel received this combination. Among those who received 131 I-MIBG after revision of the study design, one patient per dose level developed severe SOS. Rates of moderate to severe SOS at 12, 15, and 18 mCi/kg were 33.3%, 23.5%, and 25.0%, respectively. There was one toxic death. The 131 I-MIBG and 131 I-MIBG+Bu/Mel feasibility rates at the 15 mCi/kg dose level designated for further study were 96.7% (95% CI: 83.3%-99.4%) and 81.0% (95% CI: 60.0%-92.3%). CONCLUSION: This pilot trial demonstrated feasibility and tolerability of administering 131 I-MIBG followed by myeloablative therapy with Bu/Mel to newly diagnosed children with high-risk neuroblastoma in a cooperative group setting, laying the groundwork for a cooperative randomized trial (NCT03126916) testing the addition of 131 I-MIBG during induction therapy.

Longitudinal Trends in Costs for Hospitalizations at Children's Hospitals.

OBJECTIVES: Children's hospitals are increasingly focused on value-based improvement efforts to improve outcomes and lower costs. Such efforts are generally focused on improving outcomes in specific conditions. Examination of cost drivers across all admissions may facilitate strategic prioritization of efforts. METHODS: Pediatric Health Information System data set discharges from 2010 to 2017 were aggregated into services lines and billing categories. The mean annual growth per discharge as a percentage of 2010 total costs was calculated for aggregated medical and surgical service lines and 6 individual service lines with highest rates of growth. The mean annual growth per discharge for each billing category and changes in length of stay was further assessed. RESULTS: The mean annual growth in total costs was similar for aggregated medical (2.6%) and surgical (2.7%) service lines. Individual medical service lines with highest mean annual growth were oncology (3.5%), reproductive services (2.9%), and nonsurgical orthopedics (2.8%); surgical service lines with highest rate of growth were solid organ transplant (3.7%), ophthalmology (3.3%), and otolaryngology (2.9%). CONCLUSIONS: Room costs contributed most consistently to cost increases without concomitant increases in length of stay. Value-based health care initiatives must focus on room cost increases and their impacts on patient outcomes.

Is high-risk neuroblastoma induction chemotherapy possible without G-CSF? A pilot study of safety and treatment delays in the absence of primary prophylactic hematopoietic growth factors.

BACKGROUND/OBJECTIVES: Standard supportive care during induction therapy for high-risk neuroblastoma (HR-NBL) includes primary prophylactic granulocyte colony-stimulating factor (G-CSF) aimed at limiting duration of neutropenia, reducing infection risk, and minimizing treatment delays. Preclinical models suggest that G-CSF promotes maintenance of neuroblastoma cancer stem cells and may reduce the efficacy of chemotherapy. This study's objective was to determine the safety and feasibility of administering induction chemotherapy without routine use of prophylactic G-CSF. DESIGN/METHODS: Children with newly diagnosed HR-NBL received six-cycle induction chemotherapy regimen without prophylactic G-CSF in four cycles. G-CSF was administered for stem cell mobilization after cycle 3 and granulocyte-monocyte colony-stimulating factor after cycle 5 prior to surgical resection of primary disease. The primary outcome measure was the incidence of grade 3 or higher infection. We hypothesized that the per patient infection rate would be comparable to our institutional baseline rate of 58% in patients with HR-NBL receiving induction chemotherapy with prophylactic growth factor support. The trial used an A'Hern single-stage design. RESULTS: Twelve patients with HR-NBL received 58 cycles of chemotherapy on study. Three patients completed the entire six-cycle regimen with no infections. Nine patients experienced grade 3 infections (bacteremia four, urinary tract infection two, skin/soft tissue infection three). No patients experienced grade 4 infections or required intensive care treatment for infection. CONCLUSION: A greater than expected number of serious bacterial infections were observed during administration of induction chemotherapy for HR-NBL without primary prophylactic G-CSF. These results support continued prophylactic administration growth factor during induction chemotherapy.

Exome sequencing compared with standard genetic tests for critically ill infants with suspected genetic conditions.

PURPOSE: As exome sequencing (ES) is increasingly used as a diagnostic tool, we aimed to compare ES with status quo genetic diagnostic workup for infants with suspected genetic disorders in terms of identifying diagnoses, survival, and cost of care. METHODS: We studied newborns and infants admitted to intensive care with a suspected genetic etiology within the first year of life at a US quaternary-referral children's hospital over 5 years. In this propensity-matched cohort study using electronic medical record data, we compared patients who received ES as part of a diagnostic workup (ES cohort, n = 368) with clinically similar patients who did not receive ES (No-ES cohort, n = 368). RESULTS: Diagnostic yield (27.4% ES, 25.8% No-ES; p = 0.62) and 1-year survival (80.2% ES, 84.8% No-ES; p = 0.10) were no different between cohorts. ES cohort patients had higher cost of admission, diagnostic investigation, and genetic testing (all p < 0.01). CONCLUSION: ES did not differ from status quo genetic testing collectively in terms of diagnostic yield or patient survival; however, it had high yield as a single test, led to complementary classes of diagnoses, and was associated with higher costs. Further work is needed to define the most efficient use of diagnostic ES for critically ill newborns and infants.

Care of Pediatric High-Cost Hospitalizations Across Hospital Types.

BACKGROUND: High-cost hospitalizations (HCHs) account for a substantial proportion of pediatric health care expenditures. We aimed to (1) describe the distribution of pediatric HCHs across hospital types caring for children and (2) compare characteristics of pediatric HCHs by hospital type. METHODS: Cross-sectional analysis of all pediatric hospitalizations in the 2012 Kids' Inpatient Database. HCHs were defined as costs >$40 000 (94th percentile). Hospitals were categorized as children's, small general, and large general. RESULTS: Approximately 166 000 HCHs were responsible for 50.8% of aggregate hospital costs ($18.1 of $35.7 billion) and were mostly at children's hospitals (65%). Children with an HCH were largely neonates (45%), had public insurance (50%), and had ≥1 chronic condition (74%). A total of 131 children's hospitals cared for a median of 559 HCHs per hospital (interquartile range [IQR]: 355-1153) compared to 76 HCHs per hospital (IQR: 32-151) at 397 large general hospitals and 5 HCHs per hospital (IQR: 2-22) at 3581 small general hospitals. The median annual aggregate cost for HCHs was $60 million (IQR: $36-$135) per children's hospital compared to $6.6 million (IQR: $2-$15) per large general hospital and $300 000 (IQR: $116 000-$1.5 million) per small general hospital. HCHs from children's hospitals encompassed nearly 5 times as many unique clinical conditions as large general hospitals and >30 times as many as small general hospitals. CONCLUSIONS: Children's hospitals cared for a disproportionate volume, cost, and diversity of HCHs compared to general hospitals. Future studies should characterize the factors driving cost, resources, and reimbursement practices for HCH to ensure the long-term financial viability of the pediatric health care system.

Blood product administration during high risk neuroblastoma therapy.

The increasing intensity of high-risk neuroblastoma (HR NB) treatment over the last decades has resulted in improved survival at the expense of prolonging therapy and exposure to additional potentially toxic agents. Anemia and thrombocytopenia requiring transfusion are common during therapy for HR NB. Risks of cumulative red blood cell and platelet transfusions are incompletely defined in pediatric oncology patients, however, risks of transfusional iron overload are well described in other populations. This study aimed to determine the number of packed red blood cell (pRBC) and platelet transfusions throughout treatment for HR NB and how these numbers have changed with modern therapy. We performed a retrospective review of 92 patients with HR NB from June 2002 until September 2017. Patients received a median of 20 pRBC and 32 platelet transfusions. Our results demonstrated large numbers of transfusions with significantly increased blood product exposures among patients who received intensified therapy, either with additional induction chemotherapy, tandem autologous stem cell transplants, or dinutuximab plus cytokines with isotretinoin. Similar volumes of pRBC transfusions have been associated with iron overload in other populations and warrant further discussion of guidelines for long-term follow up of HR NB patients.

Using the Delphi method to identify clinicians' perceived importance of pediatric exome sequencing results.

PURPOSE: Information obtained from clinical exome sequencing (ES) may impact clinical care or other aspects of a patient's life. Little is known about clinicians' perceptions regarding either the value of ES results or which among various outcomes are most relevant to determine value. This study aims to assess clinicians' opinions of the importance of ES results for medical decision making and identify a set of outcomes to be measured in future ES evaluations. METHODS: Expert opinion regarding the value of remarkable (diagnostic/positive) and unremarkable (nondiagnostic/negative) ES results was elicited via the Delphi method, consisting of two survey rounds and a teleconference. Participants had expertise in caring for clinically diverse infants and children with suspected underlying genetic etiologies. Descriptive statistics and (dis)agreement were calculated for each survey item. RESULTS: Remarkable ES results were considered important for 17 outcome domains. Unremarkable ES results were also perceived as important in terms of psychological impact and ability to inform follow-up diagnostic test decisions. CONCLUSION: Clinicians regard remarkable ES results as more important in many ways than findings from other diagnostic modalities. Unremarkable ES results were not considered unimportant for decision making, but rather uncertain in most outcome domains.