Publications by authors named "Yuan-Shung V Huang"

22 Publications

  • Page 1 of 1

Late health outcomes after dexrazoxane treatment: A report from the Children's Oncology Group.

Cancer 2021 Oct 13. Epub 2021 Oct 13.

Oishei Children's Hospital, Roswell Park Comprehensive Center, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York.

Background: The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials.

Methods: P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods.

Results: In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m ) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35).

Conclusions: Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.
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http://dx.doi.org/10.1002/cncr.33974DOI Listing
October 2021

Broad-Spectrum Antibiotics and Risk of Graft-versus-Host Disease in Pediatric Patients Undergoing Transplantation for Acute Leukemia: Association of Carbapenem Use with the Risk of Acute Graft-versus-Host Disease

Transplant Cell Ther 2021 02 21;27(2):177.e1-177.e8. Epub 2020 Dec 21.

Center for Pediatric Clinical Effectiveness, Children's Hospital of Philadelphia, Philadelphia, PA.

Variation in the gastrointestinal (GI) microbiota after hematopoietic cell transplantation (HCT) has been associated with acute graft-versus-host disease (aGVHD). Because antibiotics induce dysbiosis, we examined the association of broad-spectrum antibiotics with subsequent aGVHD risk in pediatric patients undergoing HCT for acute leukemia. We performed a retrospective analysis in a dataset merged from 2 sources: (1) the Center for International Blood and Marrow Transplant Research, an observational transplantation registry, and (2) the Pediatric Health Information Services, an administrative database from freestanding children's hospitals. We captured exposure to 3 classes of antibiotics used for empiric treatment of febrile neutropenia: (1) broad-spectrum cephalosporins, (2) antipseudomonal penicillins, and (3) carbapenems. The primary outcome was grade II-IV aGVHD; secondary outcomes were grade III-IV aGVHD and lower GI GVHD. The adjusted logistic regression model (full cohort) and time-to-event analysis (subcohort) included transplantation characteristics, GVHD risk factors, and adjunctive antibiotic exposures as covariates. The full cohort included 2550 patients at 36 centers; the subcohort included 1174 patients. In adjusted models, carbapenems were associated with an increased risk of grade II-IV aGVHD in the full cohort (adjusted odds ratio [aOR], 1.24; 95% confidence interval [CI], 1.02 to 1.51) and subcohort (sub hazard ratio [HR], 1.31; 95% CI, 0.99 to 1.72), as well as with an increased risk of grade III-IV aGVHD (subHR, 1.77; 95% CI, 1.25 to 2.52). Early carbapenem exposure (before day 0) especially impacted aGVHD risk. For antipseudomonal penicillins, the associations with aGVHD were in the direction of increased risk but were not statistically significant. There was no identified association between broad-spectrum cephalosporins and aGVHD. Carbapenems, more than other broad-spectrum antibiotics, should be used judiciously in pediatric HCT recipients to minimize aGVHD risk. Further research is needed to clarify the mechanism underlying this association.
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http://dx.doi.org/10.1016/j.jtct.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946150PMC
February 2021

Identifying relapses and stem cell transplants in pediatric acute lymphoblastic leukemia using administrative data: Capturing national outcomes irrespective of trial enrollment.

Pediatr Blood Cancer 2021 Sep 11;68(9):e28315. Epub 2020 May 11.

Center for Childhood Cancer Research, Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Introduction: Our objectives were to design and validate methods to identify relapse and hematopoietic stem cell transplantation (HSCT) in children with acute lymphoblastic leukemia (ALL) using administrative data representing hospitalizations at US pediatric institutions.

Methods: We developed daily billing and ICD-9 code definitions to identify relapses and HSCTs within a cohort of children with newly diagnosed ALL between January 1, 2004, and December 31, 2013, previously assembled from the Pediatric Health Information System (PHIS) database. Chart review for children with ALL at the Children's Hospital of Philadelphia (CHOP) and Texas Children's Hospital (TCH) was performed to establish relapse and HSCT gold standards for sensitivity and positive predictive value (PPV) calculations. We estimated incidences of relapse and HSCT in the PHIS ALL cohort.

Results: We identified 362 CHOP and 314 TCH ALL patients in PHIS and established true positives by chart review. Sensitivity and PPV for identifying both relapse and HSCT in PHIS were > 90% at both hospitals. Five-year relapse incidence in the 10 150-patient PHIS cohort was 10.3% (95% CI 9.8%-10.9%) with 7.1% (6.6%-7.6%) of children underwent HSCTs. Patients in higher-risk demographic groups had higher relapse and HSCT rates. Our analysis also identified differences in incidences of relapse and HSCT by race, ethnicity, and insurance status.

Conclusions: Administrative data can be used to identify relapse and HSCT accurately in children with ALL whether they occur on- or off-therapy, in contrast with published approaches. This method has wide potential applicability for estimating these incidences in pediatric ALL, including patients not enrolled on clinical trials.
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http://dx.doi.org/10.1002/pbc.28315DOI Listing
September 2021

HIV Testing Among Adolescents With Acute Sexually Transmitted Infections.

Pediatrics 2020 04 16;145(4). Epub 2020 Mar 16.

Craig Dalsimer Division of Adolescent Medicine and.

Background And Objectives: Rates of sexually transmitted infections (STIs) have increased over the decade. Guidelines recommend HIV testing with incident STIs. Prevalence and factors associated with HIV testing in acute STIs are unknown in adolescents. Our objective was to determine the prevalence of completed HIV testing among adolescents with incident STIs and identify patient and health care factors associated with HIV testing.

Methods: Retrospective study of STI episodes (gonorrhea, , trichomoniasis, or syphilis) of adolescents between 13 and 24 years old from July 2014 to December 2017 in 2 urban primary care clinics. We performed mixed effects logistic regression modeling to identify patient and health care factors associated with HIV testing within 90 days of STI diagnosis.

Results: The 1313 participants contributed 1816 acute STI episodes. Mean age at STI diagnosis was 17.2 years (SD = 1.7), 75% of episodes occurred in females, and 97% occurred in African Americans. Only half (55%) of acute STI episodes had a completed HIV test. In the adjusted model, female sex, previous STIs, uninsured status, and confidential sexual health encounters were associated with decreased odds of HIV testing. Patients enrolled in primary care at the clinics, compared with those receiving sexual health care alone, and those with multipathogen STI diagnoses were more likely to have HIV testing.

Conclusions: HIV testing rates among adolescents with acute STIs are suboptimal. Patient and health care factors were found to be associated with receipt of testing and should be considered in clinical practice.
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http://dx.doi.org/10.1542/peds.2019-2265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579673PMC
April 2020

2-Year Outcomes After Complete or Staged Procedure for Tetralogy of Fallot in Neonates.

J Am Coll Cardiol 2019 09;74(12):1570-1579

Division of Cardiology, Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Philadelphia. Electronic address:

Background: There is ongoing debate about the best strategy to treat patients with tetralogy of Fallot who are symptomatic in the neonatal period.

Objectives: The aim of this study was to compare the outcomes of complete versus staged surgery (i.e., initial palliative procedure for possible later complete repair).

Methods: A retrospective cohort study was performed using the Pediatric Health Information System database, including patients who underwent complete or staged tetralogy of Fallot repair prior to 30 days of age. The primary outcome was death during 2-year follow-up after the initial procedure. Inverse probability-weighted Cox and logistic regression models were used to examine the association between surgical approach group and mortality while accounting for patient- and hospital-level factors. Causal mediation analyses examined the role of intermediate variables.

Results: A total of 2,363 patients were included (1,032 complete and 1,331 staged). There were 239 deaths. Complete neonatal repair was associated with a significantly higher risk for mortality during the 2-year follow-up period (hazard ratio: 1.51; 95% confidence interval: 1.05 to 2.06), between 7 and 30 days after the initial procedure (hazard ratio: 2.29; 95% confidence interval: 1.18 to 4.41), and during the initial hospital admission (odds ratio: 1.72; 95% confidence interval: 1.15 to 2.62). Post-operative cardiac complications were more common in the complete repair group and mediated the differences in 30-day and 2-year mortality.

Conclusions: Complete surgical repair for neonates with tetralogy of Fallot is associated with a significantly higher risk for early and 2-year mortality compared with the staged approach, after accounting for patient and hospital characteristics. Post-operative cardiac complications mediated these findings.
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http://dx.doi.org/10.1016/j.jacc.2019.05.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155423PMC
September 2019

Additional analysis of pediatric pulmonary embolism using the Pediatric Health Information System database.

Blood Adv 2019 09;3(17):2604-2607

Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1182/bloodadvances.2019000071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737405PMC
September 2019

Disparities in pediatric acute myeloid leukemia (AML) clinical trial enrollment.

Leuk Lymphoma 2019 09 7;60(9):2190-2198. Epub 2019 Feb 7.

Division of Oncology, The Children's Hospital of Philadelphia , Philadelphia , PA , USA.

Equal access to clinical trial enrollment is important to ensure that findings are generalizable to the broader population. This study aimed to evaluate disparities in enrollment on pediatric oncology clinical trials. We assessed the relationship between patient characteristics and enrollment on COG trial AAML1031 in a cohort of pediatric patients with AML in the Pediatric Health Information System. The associations of enrollment with outcomes were evaluated. Non-Hispanic Black patients, infants, and patients from zip codes with a lower proportion of poverty were less likely to enroll (30% vs. 61%,  = .004; 34% vs. 58%,  = .003; 46% vs. 58%,  = .02). On-therapy mortality was similar among enrolled and nonenrolled patients (7.3% vs. 8.9%,  = .47). Differences in early mortality were more pronounced among nonenrolled patients compared to enrolled patients (3.0% vs. 0.5%,  = .03). Understanding the etiology of these disparities will inform strategies to ensure balanced access to clinical trials across patient populations.
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http://dx.doi.org/10.1080/10428194.2019.1574002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685754PMC
September 2019

Mortality, Resource Utilization, and Inpatient Costs Vary Among Pediatric Heart Transplant Indications: A Merged Data Set Analysis From the United Network for Organ Sharing and Pediatric Health Information Systems Databases.

J Card Fail 2019 Jan 25;25(1):27-35. Epub 2018 Nov 25.

Division of Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Merging United Network for Organ Sharing (UNOS) and Pediatric Health Information Systems databases has enabled a more granular analysis of pediatric heart transplant outcomes and resource utilization. We evaluated whether transplant indication at time of transplantation was associated with mortality, resource utilization, and inpatient costs during the first year after transplantation.

Methods And Results: We analyzed transplant outcomes and resource utilization from 2004 to 2015. Patients were categorized as congenital (CHD), myocarditis, or cardiomyopathy based on UNOS-defined primary indication. CHD complexity subgroup analyses (single-ventricle, complex, and simple biventricular CHD) were also performed. Of 2251 transplants (49% CHD, 5% myocarditis, 46% cardiomyopathy), CHD recipients were younger (2 [IQR 0-10], 6 [IQR 0-12], and 7 [IQR 1-14] years, respectively; P < .001) and less likely to have a ventricular assist device (VAD) at transplantation (3%, 27%, and 13%, respectively; P < .001). Patients with single-ventricle CHD had the longest time on the waitlist and were least likely to receive a VAD before transplantation. After adjusting for patient-level factors, transplant recipients with single-ventricle CHD had the greatest mortality during transplantation admission and within 1 year (odds ratio [OR] 11.8 [95% confidence interval (CI) 5.9-23.6] and OR 6.0 [95% CI 3.6-10.2], respectively, vs cardiomyopathy). Mortality was similar between patients with myocarditis and cardiomyopathy. Post-transplantation length of stay (LOS) was longer in transplant recipients with CHD than myocarditis or cardiomyopathy (25 [interquartile range [IQR] 15-45] vs 21 [IQR 12-35] vs 16 [IQR 12-25] days; P < .001), related in part to longer duration of intensive care unit-level care (ICU LOS 8 [IQR 4-20] vs 6 [IQR 4-13] vs 5 [IQR 3-8] days; P < .001). Similarly, patients with CHD had higher median post-transplantation costs than myocarditis or cardiomyopathy ($415K [IQR $201K-503K] vs $354K [IQR $179K-390K] vs $284K [IQR $145K-319K]; P < .001) that persisted after adjusting for patient-level factors (adjusted cost ratio 1.4 [95% CI 1.4-1.5], CHD vs cardiomyopathy) and was primarily driven by longer LOS. More than 50% were readmitted during the first year after transplantation, although readmission rates were similar across transplant indications (P = .42).

Conclusions: Children with CHD, particularly single-ventricle patients, require substantially greater hospital resource utilization and have significantly worse outcomes during the first year after heart transplantation compared with other indications. Further work is aimed at identifying modifiable pre-transplantation risk factors, such as pre-transplantation conditioning with VAD support and cardiac rehabilitation, to improve post-transplantation outcomes and reduce resource utilization in this complex population.
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http://dx.doi.org/10.1016/j.cardfail.2018.11.014DOI Listing
January 2019

Hospital-Level Variability in Broad-Spectrum Antibiotic Use for Children With Acute Leukemia Undergoing Hematopoietic Cell Transplantation.

Infect Control Hosp Epidemiol 2018 07 8;39(7):797-805. Epub 2018 May 8.

2Center for Clinical Epidemiology and Biostatistics,Perelman School of Medicine at the University of Pennsylvania,Philadelphia,Pennsylvania.

OBJECTIVETo explore the prevalence and drivers of hospital-level variability in antibiotic utilization among hematopoietic cell transplant (HCT) recipients to inform antimicrobial stewardship initiatives.DESIGNRetrospective cohort study using data merged from the Pediatric Health Information System and the Center for International Blood and Marrow Transplant Research.SETTINGThe study included 27 transplant centers in freestanding children's hospitals.METHODSThe primary outcome was days of broad-spectrum antibiotic use in the interval from day of HCT through neutrophil engraftment. Hospital antibiotic utilization rates were reported as days of therapy (DOTs) per 1,000 neutropenic days. Negative binomial regression was used to estimate hospital utilization rates, adjusting for patient covariates including demographics, transplant characteristics, and severity of illness. To better quantify the magnitude of hospital variation and to explore hospital-level drivers in addition to patient-level drivers of variation, mixed-effects negative binomial models were also constructed.RESULTSAdjusted hospital rates of antipseudomonal antibiotic use varied from 436 to 1121 DOTs per 1,000 neutropenic days, and rates of broad-spectrum, gram-positive antibiotic use varied from 153 to 728 DOTs per 1,000 neutropenic days. We detected variability by hospital in choice of antipseudomonal agent (ie, cephalosporins, penicillins, and carbapenems), but gram-positive coverage was primarily driven by vancomycin use. Considerable center-level variability remained even after controlling for additional hospital-level factors. Antibiotic use was not strongly associated with days of significant illness or mortality.CONCLUSIONAmong a homogenous population of children undergoing HCT for acute leukemia, both the quantity and spectrum of antibiotic exposure in the immediate posttransplant period varied widely. Antimicrobial stewardship initiatives can apply these data to optimize the use of antibiotics in transplant patients.Infect Control Hosp Epidemiol 2018;797-805.
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http://dx.doi.org/10.1017/ice.2018.96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081961PMC
July 2018

Successful merging of data from the United Network for Organ Sharing and the Pediatric Health Information System databases.

Pediatr Transplant 2018 08 10;22(5):e13168. Epub 2018 Apr 10.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Data routinely collected through United Network for Organ Sharing (UNOS) lack the detailed information on medical resource utilization and treatment costs required to accomplish for center-level comparisons of quality of care and cost for pediatric heart transplantation. We aimed to overcome this limitation by merging UNOS with the Pediatric Health Information System (PHIS) database, an administrative database containing inpatient, emergency department, ambulatory surgery, and observation unit information from over 40 not-for-profit, tertiary care pediatric hospitals. Utilizing a probabilistic match based on center, date of birth, recipient gender, and transplant date within ±2 days, more than 90% of eligible UNOS patients (N = 2264) were successfully merged to their corresponding PHIS records. Thirty-day and 1-year mortality rates observed for the merged cohort (3.2% and 9.0%, respectively) were compared with those previously reported for pediatric heart transplants, as were the significant predictors of increased mortality. These results demonstrate that the established UNOS-PHIS cohort will provide a valid platform for subsequent research aimed at identifying center-level differences that could be exploited to optimize quality of care while minimizing cost across institutions.
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http://dx.doi.org/10.1111/petr.13168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047917PMC
August 2018

Opioid utilization among pediatric patients treated for newly diagnosed acute myeloid leukemia.

PLoS One 2018 8;13(2):e0192529. Epub 2018 Feb 8.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

Purpose: A cohort of pediatric patients with AML treated at hospitals contributing to the Pediatric Health Information System was used to evaluate differences in opioid utilization by sex, age, race, and insurance.

Methods: Billing data were used to compute the prevalence of opioid exposure and to quantify rates of utilization among those exposed to opioids as days of use per 1000 inpatient days. Multivariable regressions were used to compare opioid prevalence, and rates of utilization among those exposed.

Results: On average across courses, 95.2% of patients were exposed to analgesics, 84.7% were exposed to non-opioid analgesics and 77.7% were exposed to opioids. The proportion of opioid-exposed patients increased with age, but did not differ by gender, race, or insurance status. Analyses limited to patients exposed to opioids revealed modest differences in days of opioid use among female patients (adjusted rate ratio (aRR) = 1.19, 95% CI: 1.11, 1.28), patients <1 year (aRR = 1.37, 95% CI: 1.21, 1.55) or ≥10 years of age (aRR = 1.63, 95% CI: 1.46, 1.82), whereas Asian patients received fewer days of opioids compared with white patients (aRR = 0.76, 95% CI: 0.61, 0.95). There was moderate hospital-level variability in both the prevalence of opioid utilization overall and preference for specific opioid medications. There was greater inconsistency in practice concerning choices for supplemental and alternative opioids than in first-line opioid utilization.

Conclusion: Additional work is needed to discern whether observed differences in opioid utilization by age and race reflect a difference in treatment or a difference in the experience of pain. Future studies should also explore the factors which guide decisions on opioid selections in an attempt to explain the variability across institutions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192529PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805309PMC
April 2018

Cost comparison by treatment arm and center-level variations in cost and inpatient days on the phase III high-risk B acute lymphoblastic leukemia trial AALL0232.

Cancer Med 2018 01 23;7(1):3-12. Epub 2017 Dec 23.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

The Children's Oncology Group (COG) develops and implements multi-institutional clinical trials with the primary goal of assessing the efficacy and safety profile of treatment regimens for various pediatric cancers. However, the monetary costs of treatment regimens are not measured. AALL0232 was a COG randomized phase III trial for children with acute lymphoblastic leukemia that found that dexamethasone (DEX) was a more effective glucocorticoid than prednisone (PRED) in patients younger than 10 years, but PRED was equally effective and less toxic in older patients. In addition, high-dose methotrexate (HD-MTX) led to better survival than escalating doses of methotrexate (C-MTX). Cost data from the Pediatric Health Information System database were merged with clinical data from the COG AALL0232 trial. Total and component costs were compared between treatment arms and across hospitals. Inpatient costs were higher in the HD-MTX and DEX arms when compared to the C-MTX and PRED arms at the end of therapy. There was no difference in cost between these arms at last follow-up. Considerable variation in total costs existed across centers to deliver the same therapy that was driven by differences in inpatient days and pharmacy costs. The more effective regimens were found to be more expensive during therapy but were ultimately cost-neutral in longer term follow-up. The variations in cost across centers suggest an opportunity to standardize resource utilization for patients receiving similar therapies, which could translate into reduced healthcare expenditures.
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http://dx.doi.org/10.1002/cam4.1206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773964PMC
January 2018

Complete Versus Staged Repair for Neonates With Tetralogy of Fallot: Establishment and Validation of a Cohort of 2235 Patients Using Detailed Surgery Sequence Review of Health Care Administrative Data.

Med Care 2018 11;56(11):e76-e82

Children's Hospital of Philadelphia, Division of Cardiology.

Background: The surgical strategy for neonates with tetralogy of Fallot (TOF) consists of complete or staged repair. Assessing the comparative effectiveness of these approaches is facilitated by a large multicenter cohort. We propose a novel process for cohort assembly using the Pediatric Health Information System (PHIS), an administrative database that contains clinical and billing data for inpatient and emergency department stays from tertiary children's hospitals.

Methods: A 4-step process was used to identify neonates with TOF: (1) screen neonates in PHIS with International Classification of Diseases-9 (ICD-9) diagnosis or procedure codes for TOF; (2) include patients with TOF procedures before 30 days of age; (3) exclude patients with missing 2-year follow-up data; (4) analyze patients' 2-year surgery sequence patterns, exclude patients inconsistent with a treatment strategy for TOF, and designate patients as complete or staged repair. Manual chart review at 1 PHIS center was performed to validate this process.

Results: Between January 2004 and March 2015, 5862 patients were identified in step 1. Step 2 of cohort assembly excluded 3425 patients (58%); step 3 excluded 148 patients (3%); and step 4 excluded 54 patients (1%). The final cohort consisted of 2235 neonates with TOF from 45 hospitals. Manual chart review of 336 patients showed a positive predictive value for accurate PHIS identification of 44% after step 1 and 97% after step 4.

Conclusions: This systematic cohort identification algorithm resulted in a high positive predictive value to appropriately categorize patients. This carefully assembled cohort offers a unique opportunity for future studies in neonatal TOF outcomes.
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http://dx.doi.org/10.1097/MLR.0000000000000846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615470PMC
November 2018

Burden of Influenza-Related Hospitalizations and Attributable Mortality in Pediatric Acute Lymphoblastic Leukemia.

J Pediatric Infect Dis Soc 2015 Dec 22;4(4):290-6. Epub 2014 Jul 22.

Oncology Center for Pediatric Clinical Effectiveness, The Children's Hospital of Philadelphia, Pennsylvania Department of Pediatrics Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Background: Influenza can be severe in patients with underlying malignancy; however, the rate of influenza hospitalizations and attributable mortality in children with cancer is unknown.

Methods: We performed a retrospective cohort study among 10 698 children with new-onset acute lymphoblastic leukemia (ALL) from 41 US children's hospitals between January 1999 and September 2011. Influenza-related hospitalizations were identified using ICD-9 discharge diagnosis codes, excluding hospitalizations during low-prevalence influenza periods. Follow-up was censored at the earliest of 5 events: end of study period, expected end of chemotherapy, last known hospitalization, hematopoietic stem cell transplant, or death. Data were collected on hospitalization characteristics and resource utilization. Hospitalization rates were calculated using season-adjusted person-time. Crude attributable in-hospital mortality was calculated using baseline mortality for noninfluenza hospitalizations during the same period. Subgroup analysis was performed by time from ALL diagnosis and by age category.

Results: The rate of influenza-related hospitalizations was 618.3 per 100 000 person-months. Rates were similar by time from ALL diagnosis and across age categories. Overall attributable in-hospital mortality was 1.0% (95% confidence interval [CI], 0.3%-2.3%) and was highest for children <6 months from diagnosis (1.6%; 95% CI, 0.4%-4.5%) and children <2 years of age (6.7%; 95% CI, 1.3%-22.7%). Total length of stay, days of broad-spectrum antibiotic exposure, and duration of intensive care were significantly greater for influenza-related hospitalizations compared with noninfluenza hospitalizations.

Conclusions: The burden of influenza-related hospitalizations in children with ALL is high and associated with significantly increased resource utilization and attributable mortality.
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http://dx.doi.org/10.1093/jpids/piu066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681386PMC
December 2015

A Multicenter Cohort Study of Inferior Vena Cava Filter Use in Children.

Pediatr Blood Cancer 2015 Dec 23;62(12):2089-93. Epub 2015 Jul 23.

Divisions of Hematology, Departments of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: To describe inferior vena cava (IVC) filter use in pediatric patients admitted to U.S. children's hospitals and to determine factors associated with prophylactic placement.

Procedure: This retrospective multicenter cohort study utilized data from the Pediatric Health Information Systems (PHIS) administrative database, with 44 participating children's hospitals. Subjects included for analysis were less than 21 years of age, admitted to a PHIS hospital between January 1, 2004 and December 31, 2012 and had a procedure code for IVC filter placement. ICD-9-CM discharge codes were used to identify subjects with a venous thromboembolism (VTE). Pharmaceutical billing codes were used to identify anticoagulation use.

Results: During this 9-year-study period, 276 subjects met the inclusion criteria. The median age of subjects was 15 years (range 1 month-20 years). Subjects had an ICD-9-CM code for VTE 76% of the time and were started on anticoagulation after IVC filter placement 77% of the time. The mean number of IVC filters placed per year was 6 per 100,000 admissions (SD-1.4), which was constant throughout the study period (P = 0.12). The median number of filters placed by center was 4.5 (range 0-32). In multivariate analysis, subjects undergoing orthopedic surgery were more likely to have prophylactic placement of an IVC filter (OR 4.5; 95%CI 1.8-11).

Conclusions: IVC filter placement in pediatric patients remains a rare event and is most common in adolescents. Unlike in adults, pediatric IVC filter placement does not appear to be increasing over time and is predominantly used in the setting of a venous thrombotic event.
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http://dx.doi.org/10.1002/pbc.25662DOI Listing
December 2015

Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric oncology patients.

Pediatr Blood Cancer 2015 Apr 26;62(4):704-9. Epub 2014 Mar 26.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Dexrazoxane may reduce anthracycline-associated cardiotoxicity in pediatric cancer patients. However, concerns of secondary acute myeloid leukemia (AML) have led to restrictions on pediatric dexrazoxane use in Europe. Published data about dexrazoxane-associated secondary AML are limited and conflicting. We sought to estimate the secondary AML risk in children receiving dexrazoxane after anthracycline exposure.

Procedure: A retrospective cohort of children with newly identified malignancies (excluding AML) receiving anthracyclines between January 1, 1999 and March 31, 2011 was established using the Pediatric Health Information System (PHIS). Patients were followed for all subsequent admissions to identify dexrazoxane exposures and secondary AML, defined by AML ICD-9 codes and AML induction chemotherapy. Logistic regression was used to model the association of dexrazoxane and secondary AML risk. A propensity score was used to adjust for measurable confounding.

Results: Of 15,532 patients in the cohort exposed to anthracyclines, 1,406 received dexrazoxane. The secondary AML rate was 0.21% (3 of 1,046) in dexrazoxane-exposed and 0.55% (77 of 14,126) in unexposed patients. In a propensity score-adjusted multivariate analysis, dexrazoxane exposure was not associated with an increased risk of secondary AML, OR = 0.38, 95% CI 0.11-1.26.

Conclusions: Dexrazoxane was not associated with an increased risk of secondary AML in a large cohort of pediatric cancer patients receiving anthracyclines in US hospitals. While these data support dexrazoxane's safety in the general pediatric oncology population, additional studies are needed to confirm these findings and to quantify dexrazoxane's long-term cardioprotective effects.
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http://dx.doi.org/10.1002/pbc.25043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177031PMC
April 2015

Patient and hospital factors associated with induction mortality in acute lymphoblastic leukemia.

Pediatr Blood Cancer 2014 May 19;61(5):846-52. Epub 2013 Nov 19.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Deaths during induction chemotherapy for pediatric acute lymphoblastic leukemia (ALL) account for one-tenth of ALL-associated mortality and half of ALL treatment-related mortality. We sought to ascertain patient- and hospital-level factors associated with induction mortality.

Procedure: We performed a retrospective cohort analysis of 8,516 children ages 0 to <19 years with newly diagnosed ALL admitted to freestanding US children's hospitals from 1999 to 2009 using the Pediatric Health Information System database. Induction mortality risk was modeled accounting for demographics, intensive care unit-level interventions, and socioeconomic status (SES) using Cox regression. The association of ALL induction mortality with hospital-level factors including volume, hospital-wide mortality and payer mix was analyzed with multiple linear regression.

Results: ALL induction mortality was 1.12%. Race and patient-level SES factors were not associated with induction mortality. Patients receiving both mechanical ventilation and vasoactive infusions experienced nearly 50% mortality (hazard ratio 122.30, 95% CI 66.56-224.80). Institutions in the highest induction mortality quartile contributed 27% of all patients but nearly half of all deaths (47 of 95). Hospital payer mix was associated with ALL induction mortality after adjustment for other hospital-level factors (P = 0.046).

Conclusions: The overall risk of induction death is low but substantially increased in patients with cardio-respiratory and other organ failures. Induction mortality varies up to three-fold across hospitals and is correlated with hospital payer mix. Further work is needed to improve induction outcomes in hospitals with higher mortality. These data suggest an induction mortality rate of less than 1% may be an attainable national benchmark.
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http://dx.doi.org/10.1002/pbc.24855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951664PMC
May 2014

Zoonotic infections in pediatric patients with acute leukemia.

Pediatr Blood Cancer 2013 Dec 19;60(12):E160-2. Epub 2013 Aug 19.

Drexel University School of Public Health, Philadelphia, Pennsylvania.

Few studies have described the impact of zoonotic diseases in children with leukemia. This study aimed to describe the frequency of and associated demographic factors for zoonotic diseases in pediatric acute leukemia patients. Descriptive and comparative statistics relative to age, sex, and patient region were performed on an assembled 11-year retrospective cohort of acute leukemia patients. Of 10,197 patients, 88 patients (0.86%) were found to have a zoonotic infection. Gastrointestinal diseases were the most commonly (86.4%) identified zoonotic illnesses. Although rare, zoonotic diseases do occur in children with leukemia and frequency varies by age, region, and gender.
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http://dx.doi.org/10.1002/pbc.24596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915061PMC
December 2013

Variation in hospital antibiotic prescribing practices for children with acute lymphoblastic leukemia.

Leuk Lymphoma 2013 Aug 26;54(8):1633-9. Epub 2012 Dec 26.

Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. fi

Antibiotic variation among pediatric oncology patients has not been well-described. Identification of significant variability in antibiotic use within this population would warrant evaluation of its clinical impact. We conducted a retrospective cohort study of newly diagnosed patients with pediatric acute lymophoblastic leukemia (ALL) hospitalized from 1999 to 2009 in 39 freestanding US children's hospitals within the Pediatric Health Information System. Medication use data were obtained for the first 30 days from each patient's index ALL admission date. Antibiotic exposure rates were reported as antibiotic days/1000 hospital days. Unadjusted composite broad-spectrum antibiotic exposure rates varied from 577 to 1628 antibiotic days/1000 hospital days. This wide range of antibiotic exposure was unaffected by adjustment for age, gender, race and days of severe illness (adjusted range: 532-1635 days of antibiotic therapy/1000 hospital days). Antibiotic use for children with newly diagnosed ALL varies widely across children's hospitals and is not explained by demographics or illness severity.
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http://dx.doi.org/10.3109/10428194.2012.750722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906846PMC
August 2013

Dexrazoxane use in pediatric patients with acute lymphoblastic or myeloid leukemia from 1999 and 2009: analysis of a national cohort of patients in the Pediatric Health Information Systems database.

Pediatr Blood Cancer 2013 Apr 4;60(4):616-20. Epub 2012 Sep 4.

Division of Oncology, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

Background: Acute lymphoblastic (ALL) and myeloid leukemia (AML) account for approximately 26% of pediatric cancers. Anthracyclines are widely used to treat these leukemias, but dosing is limited by cardiotoxicity. Data support the efficacy of dexrazoxane as a cardioprotectant in children; however, dexrazoxane use in children is not universally accepted due to concerns about toxicity, impact on the antitumor effect of anthracyclines, and risk of secondary malignant neoplasms (SMN).

Procedure: We conducted a retrospective cohort study to describe patterns of dexrazoxane use in pediatric patients with ALL or AML using the Pediatric Health Information Systems (PHIS) database. Patients identified as having de novo ALL and AML at these PHIS hospitals were included.

Results: Of 8,733 patients with ALL and 2,556 with AML, 207 (2.4%) and 52 (2.0%) received dexrazoxane, respectively. Dexrazoxane use was greater in older children with ALL and AML and in black patients and males with ALL. Dexrazoxane use varied across time and by region in ALL, but not in AML. Prescribing practices differed across institutions and most patients received the first dose early or late after the start of leukemia treatment.

Conclusions: Dexrazoxane administration is limited in patients with ALL and AML and prescribing practices vary across the country. Further work is necessary to understand how dexrazoxane is used in patients at highest risk of developing cardiotoxicity and to define its true effect on the development of SMNs.
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http://dx.doi.org/10.1002/pbc.24270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918414PMC
April 2013

Establishment of an 11-year cohort of 8733 pediatric patients hospitalized at United States free-standing children's hospitals with de novo acute lymphoblastic leukemia from health care administrative data.

Med Care 2014 Jan;52(1):e1-6

*Division of Infectious Diseases †Center for Pediatric Clinical Effectiveness, The Children's Hospital of Philadelphia ‡Department of Pediatrics §Center for Clinical Epidemiology and Biostatistics, the Perelman School of Medicine at the University of Pennsylvania ∥Division of Oncology, The Children's Hospital of Philadelphia ¶Department of Biostatistics and Epidemiology, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Background: Acute lymphoblastic leukemia (ALL) accounts for almost one quarter of pediatric cancer in the United States. Despite cooperative group therapeutic trials, there remains a paucity of large cohort data on which to conduct epidemiology and comparative effectiveness research studies.

Research Design: We designed a 3-step process utilizing International Classification of Diseases-9 Clinical Modification (ICD-9) discharge diagnoses codes and chemotherapy exposure data contained in the Pediatric Health Information System administrative database to establish a cohort of children with de novo ALL. This process was validated by chart review at 1 of the pediatric centers.

Results: An ALL cohort of 8733 patients was identified with a sensitivity of 88% [95% confidence interval (CI), 83%-92%] and a positive predictive value of 93% (95% CI, 89%-96%). The 30-day all cause inpatient case fatality rate using this 3-step process was 0.80% (95% CI, 0.63%-1.01%), which was significantly different than the case fatality rate of 1.40% (95% CI, 1.23%-1.60%) when ICD-9 codes alone were used.

Conclusions: This is the first report of assembly and validation of a cohort of de novo ALL patients from a database representative of free-standing children's hospitals across the United States. Our data demonstrate that the use of ICD-9 codes alone to establish cohorts will lead to substantial patient misclassification and result in biased outcome estimates. Systematic methods beyond the use of just ICD-9 codes must be used before analysis to establish accurate cohorts of patients with malignancy. A similar approach should be followed when establishing future cohorts from administrative data.
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http://dx.doi.org/10.1097/MLR.0b013e31824deff9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381055PMC
January 2014

Widespread use of fresh frozen plasma in US children's hospitals despite limited evidence demonstrating a beneficial effect.

J Pediatr 2012 Feb 14;160(2):210-215.e1. Epub 2011 Sep 14.

Department of Pediatrics, Division of Hematology/Oncology, Saint Louis University, Cardinal Glennon Children's Medical Center, St Louis, MO 63104, USA.

Objectives: To determine the pattern, prevalence and potential complications of fresh frozen plasma (FFP) use in US pediatric hospitals from 2002-2009.

Study Design: Retrospective cohort study using the Pediatric Health Information System (PHIS) administrative database, which was queried for FFP admissions using diagnostic, procedural, and billing codes. Demographic data, daily use, and procedural codes were used to describe the patient population and pattern of FFP use.

Results: Of 3 252 149 PHIS-recorded admissions, 2.85% had codes consistent with FFP use. This percentage did not change over the course of the study (P=.10). FFP was most commonly administered to children <1 year of age (54%), critically ill children (70%), and those with heart disease (34%). Fifteen percent of FFP-related admissions involved a thrombotic event. The overall mortality rate was 17% and it decreased during the study (P<.001). There was noteworthy variation in the proportion of FFP admissions among participating institutions.

Conclusions: FFP is commonly used in children admitted to PHIS hospitals. Despite recent expert recommendations highlighting the lack of efficacy in many clinical scenarios, the rate of FFP use does not appear to be changing. Randomized, controlled studies are needed to determine appropriate indications for FFP use and evaluate for potential complications.
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http://dx.doi.org/10.1016/j.jpeds.2011.08.013DOI Listing
February 2012
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