Association of the social disorganization index with time to first septic shock event in children with acute myeloid leukemia.

BACKGROUND: Pediatric acute myeloid leukemia (AML) chemotherapy increases the risk of life-threatening complications, including septic shock (SS). An area-based measure of social determinants of health, the social disorganization index (SDI), was hypothesized to be associated with SS and SS-associated death (SS-death). METHODS: Children treated for de novo AML on two Children's Oncology Group trials at institutions contributing to the Pediatric Health Information System (PHIS) database were included. The SDI was calculated via residential zip code data from the US Census Bureau. SS was identified via PHIS resource utilization codes. SS-death was defined as death within 2 weeks of an antecedent SS event. Patients were followed from 7 days after the start of chemotherapy until the first of end of front-line therapy, death, relapse, or removal from study. Multivariable-adjusted Cox regressions estimated hazard ratios (HRs) comparing time to first SS by SDI group. RESULTS: The assembled cohort included 700 patients, with 207 (29.6%) sustaining at least one SS event. There were 233 (33%) in the SDI-5 group (highest disorganization). Adjusted time to incident SS did not statistically significantly differ by SDI (reference, SDI-1; SDI-2: HR, 0.84 [95% confidence interval (CI), 0.51-1.41]; SDI-3: HR, 0.70 [95% CI, 0.42-1.16]; SDI-4: HR, 0.97 [95% CI, 0.61-1.53]; SDI-5: HR, 0.72 [95% CI, 0.45-1.14]). Nine patients (4.4%) with SS experienced SS-death; seven of these patients (78%) were in SDI-4 or SDI-5. CONCLUSIONS: In a large, nationally representative cohort of trial-enrolled pediatric patients with AML, there was no significant association between the SDI and time to SS.

Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children's Oncology Group AAML1331 Trial.

IMPORTANCE: All-trans retinoic acid (ATRA) and arsenic trioxide therapy without the use of maintenance therapy has been found to be beneficial for the treatment of adults with standard-risk acute promyelocytic leukemia (APL). However, it is unclear whether similar regimens are safe and beneficial for the treatment of high-risk APL or pediatric patients with standard-risk APL. OBJECTIVE: To assess whether treatment with an ATRA and arsenic trioxide-based regimen is safe and allows for the elimination or substantial reduction of chemotherapy use among pediatric patients with standard-risk or high-risk APL, respectively. DESIGN, SETTING, AND PARTICIPANTS: The Children's Oncology Group AAML1331 study is a nonrandomized, noninferiority trial that examined survival outcomes among 154 pediatric patients with APL compared with a historical control group of patients with APL from the AAML0631 study. Patients aged 1 to 21 years were enrolled at 85 pediatric oncology centers (members of the Children's Oncology Group) in Australia, Canada, and the US from June 29, 2015, to May 7, 2019, with follow-up until October 31, 2020. All patients had newly diagnosed APL and were stratified into standard-risk APL (white blood cell count <10 000/µL) and high-risk APL (white blood cell count ≥10 000/µL) cohorts. INTERVENTIONS: All patients received ATRA and arsenic trioxide continuously during induction therapy and intermittently during 4 consolidation cycles. Patients with high-risk APL received 4 doses of idarubicin during induction therapy only. The duration of therapy was approximately 9 months, and no maintenance therapy was administered. MAIN OUTCOMES AND MEASURES: Event-free survival (EFS) at 2 years after diagnosis. RESULTS: Among 154 patients (median age, 14.4 years [range, 1.1-21.7 years]; 81 male participants [52.6%]) included in the analysis, 98 patients (63.6%) had standard-risk APL, and 56 patients (36.4%) had high-risk APL. The median follow-up duration was 24.7 months (range, 0-49.5 months) for patients with standard-risk APL and 22.8 months (range, 0-47.7 months) for patients with high-risk APL. Patients with standard-risk APL had a 2-year EFS rate of 98.0% and an overall survival rate of 99.0%; adverse events included 1 early death during induction therapy and 1 relapse. Patients with high-risk APL had a 2-year EFS rate of 96.4% and an overall survival rate of 100%; adverse events included 2 relapses and 0 deaths. These outcomes met predefined noninferiority criteria (noninferiority margin of 10% among those with standard-risk APL and 14.5% among those with high-risk APL). CONCLUSIONS AND RELEVANCE: In this nonrandomized, noninferiority trial, pediatric patients with standard-risk APL who received treatment with a chemotherapy-free ATRA and arsenic trioxide regimen experienced positive outcomes. Patients with high-risk APL also had positive outcomes when treated with a novel ATRA and arsenic trioxide-based regimen that included 4 doses of idarubicin during induction therapy only and no maintenance therapy. The 2-year EFS estimates were noninferior to the historical comparator group, and advantages of the regimen included shorter treatment duration, lower exposure to anthracycline and intrathecal chemotherapy, and fewer days hospitalized. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02339740.

The cost-effectiveness of human papillomavirus self-collection among cervical cancer screening non-attenders in El Salvador.

Cervical cancer screening with human papillomavirus (HPV) DNA testing has been incorporated into El Salvador's national guidelines. The feasibility of home-based HPV self-collection among women who do not attend screening at the clinic (i.e., non-attenders) has been demonstrated, but cost-effectiveness has not been evaluated. Using cost and compliance data from El Salvador, we informed a mathematical microsimulation model of HPV infection and cervical carcinogenesis to conduct a cost-effectiveness analysis from the societal perspective. We estimated the reduction in cervical cancer risk, lifetime cost per woman (2017 US$), life expectancy, and incremental cost-effectiveness ratio (ICER, 2017 US$ per year of life saved [YLS]) of a program with home-based self-collection of HPV (facilitated by health promoters) for the 18% of women reluctant to screen at the clinic. The model was calibrated to epidemiologic data from El Salvador. We evaluated health and economic outcomes of the self-collection intervention for women aged 30 to 59 years, alone and in concert with clinic-based HPV provider-collection. Home-based self-collection of HPV was projected to reduce population cervical cancer risk by 14% and cost $1210 per YLS compared to no screening. An integrated program reaching 99% coverage with both provider- and home-based self-collection of HPV reduced cancer risk by 74% (compared to no screening), and cost $1210 per YLS compared to provider-collection alone. Self-collection facilitated by health promoters is a cost-effective strategy for increasing screening uptake in El Salvador.

Comparison of in-patient costs for children treated on the AAML0531 clinical trial: A report from the Children's Oncology Group.

BACKGROUND: A better understanding of drivers of treatment costs may help identify effective cost containment strategies and prioritize resources. We aimed to develop a method for estimating inpatient costs for pediatric patients with acute myeloid leukemia (AML) enrolled on NCI-funded Phase III trials, compare costs between AAML0531 treatment arms (standard chemotherapy ± gemtuzumab ozogamicin (GMTZ)), and evaluate primary drivers of costs for newly diagnosed pediatric AML. PROCEDURE: Patients from the AAML0531 trial were matched on hospital, sex, and dates of birth and diagnosis to the Pediatric Health Information Systems (PHIS) database to obtain daily billing data. Inpatient treatment costs were calculated as adjusted charges multiplied by hospital-specific cost-to-charge ratios. Generalized linear models were used to compare costs between treatment arms and courses, and by patient characteristics. RESULTS: Inpatient costs did not differ by randomized treatment arm. Costs varied by course with stem cell transplant being most expensive, followed by Intensification II (cytarabine/mitoxantrone) and Induction I (cytarabine/daunorubicin/etoposide). Room/board and pharmacy were the largest contributors to inpatient treatment cost, representing 74% of the total cost. Higher AML risk group (P = 0.0003) and older age (P < 0.0001) were associated with significantly higher daily inpatient cost. CONCLUSIONS: Costs from external data sources can be successfully integrated into NCI-funded Phase III clinical trials. Inpatient treatment costs did not differ by GMTZ exposure but varied by chemotherapy course. Variation in cost by course was driven by differences in duration of hospitalization through room/board charges as well as increased clinical and pharmacy charges in specific courses.

Reducing decision errors in the paired comparison of the diagnostic accuracy of screening tests with Gaussian outcomes.

BACKGROUND: Scientists often use a paired comparison of the areas under the receiver operating characteristic curves to decide which continuous cancer screening test has the best diagnostic accuracy. In the paired design, all participants are screened with both tests. Participants with suspicious results or signs and symptoms of disease receive the reference standard test. The remaining participants are classified as non-cases, even though some may have occult disease. The standard analysis includes all study participants, which can create bias in the estimates of diagnostic accuracy since not all participants receive disease status verification. We propose a weighted maximum likelihood bias correction method to reduce decision errors. METHODS: Using Monte Carlo simulations, we assessed the method's ability to reduce decision errors across a range of disease prevalences, correlations between screening test scores, rates of interval cases and proportions of participants who received the reference standard test. RESULTS: The performance of the method depends on characteristics of the screening tests and the disease and on the percentage of participants who receive the reference standard test. In studies with a large amount of bias in the difference in the full areas under the curves, the bias correction method reduces the Type I error rate and improves power for the correct decision. We demonstrate the method with an application to a hypothetical oral cancer screening study. CONCLUSION: The bias correction method reduces decision errors for some paired screening trials. In order to determine if bias correction is needed for a specific screening trial, we recommend the investigator conduct a simulation study using our software.

Generalization of Youden index for multiple-class classification problems applied to the assessment of externally validated cognition in Parkinson disease screening.

Routine cognitive screening in Parkinson disease (PD) has become essential for management, to track progression and to assess clinical status in therapeutic trials. Patients with mild cognitive impairment (PD-MCI) are more likely to progress to dementia and therefore need to be distinguished from patients with normal cognition and those with dementia. A three-class Youden index has been recently proposed to select cut-off points in three-class classification problems. In this article, we examine properties of a modification of the three-class Youden index and propose a generalization to k-class classification problems. Geometric and theoretical properties of the modified index J(k) are examined. It is shown that J(k) is equivalent to the sum of the k - 1 two-class Youden indices for the adjacent classes of the ordered alternative problem given that the ordering holds. Methods are applied in the assessment of the Montreal Cognitive Assessment test when screening cognition in PD.

Digital assessment of the reproductive tract versus colposcopy for directing biopsies in women with abnormal Pap smears.

OBJECTIVE: This study aimed to compare digital camera assessment of the reproductive tract (DART) to colposcopy for the evaluation of abnormal Pap smears. MATERIALS AND METHODS: Participants included 207 women with abnormal Pap smears. Colposcopy and DART were performed on each patient by separate examiners with the goal of lesion detection. Analysis was performed per patient and per biopsy. RESULTS: Patients had an average of 2.9 biopsies. Forty-two patients and 81 biopsies were positive for cervical intraepithelial neoplasia 2+. Both DART and colposcopy detected 41 (97.6%) of 42 patients (95% CI = 85.9%-99.9%). Digital camera assessment of the reproductive tract detected 66/81 (81.4%; CI = 70.7%-88.9%) and colposcopy detected 69/81 (85.2%; CI = 73.2%-92.4%) of biopsies that were cervical intraepithelial neoplasia 2+. CONCLUSIONS: Digital camera assessment of the reproductive tract detects high-grade lesions of the cervix with similar sensitivity to colposcopy. It holds great promise to expand cervical cancer precursor lesion detection in areas with limited resources.

A receiver operating characteristic analysis approach for the assessment of the separation of female Mediterranean fruit fly (Diptera: Tephritidae) oviposition distributions.

Average fecundity rates and survival are the main components of fitness estimates in studies comparing performance of insect populations. Reproduction is inherently age related in most insect species, and age-specific offspring production is very important in determining fitness components. However, comparison of age-specific reproduction rates are not straight forward and most studies limit analyses to comparisons of average fecundity rates and survival as the main components of the performance of insect populations. We develop a receiver operating characteristic (ROC) curve approach to compare lifetime oviposition distributions. We use empirical data of a study of Mediterranean fruit fly, Ceratitis capitata (Wiedemann) (Diptera: Tephritidae) populations, where each fly's lifetime oviposition distribution was recorded for samples studied in natural and artificial oviposition substrates. Currently, there exists no routinely used methodology for the comparison of oviposition distributions and assessment of their separation. ROC analysis is regularly used in two-sample problems in medical biostatistics when the main task is depiction and quantification of the separation of the empirical distributions from which the data arise. Adaptation of such an analysis to our data has shown that age-specific egg-laying distributions can differ, whereas average fecundity rates do not. Therefore, ROC analysis provides a method of gaining insight in the biological process of egg-laying patterns in relatively long-lived insects with many practical and theoretical implications in entomological experimentation.

Comparing accuracy in an unpaired post-market device study with incomplete disease assessment.

The sensitivity and specificity of a new medical device are often compared relative to that of an existing device by calculating ratios of sensitivities and specificities. Although it would be ideal for all study subjects to receive the gold standard so true disease status was known for all subjects, it is often not feasible or ethical to obtain disease status for everyone. This paper proposes two unpaired designs where each subject is only administered one of the devices and device results dictate which subjects are to receive disease verification. Estimators of the ratio of accuracy and corresponding confidence intervals are proposed for these designs as well as sample size formulae. Simulation studies are performed to investigate the small sample bias of the estimators and the performance of the variance estimators and sample size formulae. The sample size formulae are applied to the design of a cervical cancer study to compare the accuracy of a new device with the conventional Pap smear.

Comparison of ROC umbrella volumes with an application to the assessment of lung cancer diagnostic markers.

Receiver operating characteristic (ROC) analysis is widely used to assess the ability of diagnostic markers to correctly classify into one of two disease classes. ROC surfaces and umbrella surfaces generalize the utility of ROC analysis when there are three disease classes. Identification of lung cancer diagnostic markers is an active area of research since prognosis for those diagnosed with lung cancer is so poor and there is not an accurate method for early detection of lung cancer. A study conducted for the assessment of DNA methylation markers motivated the comparison of ROC umbrella surfaces which is developed in this article using U-statistics and bootstrap methodology.

A novel design for estimating relative accuracy of screening tests when complete disease verification is not feasible.

The accuracy (sensitivity and specificity) of a new screening test can be compared with that of a standard test by applying both tests to a group of subjects in which disease status can be determined by a gold standard (GS) test. However, it is not always feasible to administer a GS test to all study subjects. For example, a study is planned to determine whether a new screening test for cervical cancer ("ThinPrep") is better than the standard test ("Pap"), and in this setting it is not feasible (or ethical) to determine disease status by biopsy in order to identify women with and without disease for participation in a study. When determination of disease status is not possible for all study subjects, the relative accuracy of two screening tests can still be estimated by using a paired screen-positive (PSP) design in which all subjects receive both screening tests, but only have the GS test if one of the screening tests is positive. Unfortunately in the cervical cancer example, the PSP design is also infeasible because it is not technically possible to administer both the ThinPrep and Pap at the same time. In this article, we describe a randomized paired screen-positive (RPSP) design in which subjects are randomized to receive one of the two screening tests initially, and only receive the other screening test and GS if the first screening test is positive. We derive maximum likelihood estimators and confidence intervals for the relative accuracy of the two screening tests, and assess the small sample behavior of these estimators using simulation studies. Sample size formulae are derived and applied to the cervical cancer screening trial example, and the efficiency of the RPSP design is compared with other designs.