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Definitive clinical trials are resource intensive, often requiring a large number of participants over several years. One approach to improve the efficiency of clinical trials is to incorporate historical information into the primary trial analysis. This approach has tremendous potential in the areas of pediatric or rare disease trials, where achieving reasonable power is difficult. In this article, we introduce a novel Bayesian group‐sequential trial design based on Multisource Exchangeability Models, which allows for dynamic borrowing of historical information at the interim analyses. Our approach achieves synergy between group sequential and adaptive borrowing methodology to attain improved power and reduced sample size. We explore the frequentist operating characteristics of our design through simulation and compare our method to a traditional group‐sequential design. Our method achieves earlier stopping of the primary study while increasing power under the alternative hypothesis but has a potential for type I error inflation under some null scenarios. We discuss the issues of decision boundary determination, power and sample size calculations, and the issue of information accrual. We present our method for a continuous and binary outcome, as well as in a linear regression setting. [ABSTRACT FROM AUTHOR]

The increasing multiplicity of data sources offers exciting possibilities in estimating the effects of a treatment, intervention, or exposure, particularly if observational and experimental sources could be used simultaneously. Borrowing between sources can potentially result in more efficient estimators, but it must be done in a principled manner to mitigate increased bias and Type I error. Furthermore, when the effect of treatment is confounded, as in observational sources or in clinical trials with noncompliance, causal effect estimators are needed to simultaneously adjust for confounding and to estimate effects across data sources. We consider the problem of estimating causal effects from a primary source and borrowing from any number of supplemental sources. We propose using regression‐based estimators that borrow based on assuming exchangeability of the regression coefficients and parameters between data sources. Borrowing is accomplished with multisource exchangeability models and Bayesian model averaging. We show via simulation that a Bayesian linear model and Bayesian additive regression trees both have desirable properties and borrow under appropriate circumstances. We apply the estimators to recently completed trials of very low nicotine content cigarettes investigating their impact on smoking behavior. [ABSTRACT FROM AUTHOR]

Few prognostic models have been created in children that receive liver retransplantation (rLT). We examined the SRTR database of 731 children that underwent second liver transplant between 2002 and 2018. Proportional hazards models using backward variable selection were used to identify recipient, donor, and surgical characteristics associated with survival. A simple prognostic scoring system or nomogram (ie, each risk factor was weighted on a five-point scale) was constructed based on the fitted model. Recipient age (P < .001), MELD/PELD (P < .001), recipient ventilated (P = .003), donor cause of death (P = .024), graft type (P = .045), first graft loss due to biliary tract complications (P = .048), and survival time of the first graft (P = .006) were significant predictors of retransplant survival. The bias-corrected Harrell's C-index for the multivariable model was 0.63. Survival was significantly different (P < .001) for those at low risk (0-4 points), medium risk (5-7 points), and high risk (8+ points). Survival was equivalent between low risk pediatric second transplant recipients and pediatric primary liver transplant recipients (P = .67) but significantly worse for medium- (P < .001) and high-risk (P < .001) recipients. With simple clinical characteristics, this scoring tool can modestly discriminate between those children at high risk and those children at low risk of poor outcomes after second liver transplant. [ABSTRACT FROM AUTHOR]

Summary: Background: Obesity is a heterogeneous disease with variable treatment response. Identification of the unique constellation of contributors to obesity may allow for targeted interventions and improved outcomes. Objective: Identify empirically derived phenotypes of pediatric patients with obesity based on appetitive and psychological correlates of obesity. Methods: This cross‐sectional study included patients aged 5–12 years who were treated in a weight management clinic and completed standard intake questionnaires including Child Eating Behavior Questionnaire (CEBQ), Vanderbilt ADHD Scale and Pediatric Symptom Checklist. Phenotypes were elicited using latent profile analysis of 12 indicators: eight CEBQ subscales, inattention, hyperactivity/impulsivity, internalizing and externalizing symptoms. Results: Parents/guardians of 384 patients (mean age 9.8 years, mean BMI 30.3 kg/m2) completed the intake questionnaires. A 4‐phenotype model best fits the data. Hedonic Impulsive phenotype (42.5%) exhibited high food enjoyment and hyperactivity/impulsivity. Inattentive Impulsive phenotype (27.4%) exhibited overall low food approach and high food avoid behaviours, and highest inattention. Hedonic Emotional phenotype (20.8%) scored the highest on food enjoyment, internalizing and externalizing symptoms. Picky Eating phenotype (9.3%) scored the lowest on food approach, inattention, hyperactivity/impulsivity, internalizing and externalizing symptoms. Conclusion: Appetitive traits and psychological symptoms appear to cluster in distinct patterns, giving rise to four unique phenotypic profiles, which, if replicated, may help inform the development of tailored treatment plans. [ABSTRACT FROM AUTHOR]

Background: The optimal age of kidney transplantation for infants and toddlers with kidney failure is unclear. We aimed to evaluate the patient survival associated with kidney transplantation before 2 years of age versus remaining on the waitlist until ≥2 years. Method: We used the Scientific Registry of Transplant Recipients to identify all children added to the deceased‐donor waitlist before 2 years of age between 1/1/2000 and 4/30/2020. For each case aged <2 years at transplant, we created a control group comprising all candidates on the waitlist on the case's transplant date. Patient survival was evaluated using sequential Cox regression. Dialysis‐free time was defined as graft survival time for cases and the sum of dialysis‐free time on the waitlist and graft survival time for controls. Results: We observed similar patient survival for posttransplant periods 0–3 and 4–12 months but higher survival for period >12 months for <2‐year decreased‐donor recipients (aHR: 0.32; 95% CI: 0.13–0.78; p =.01) compared with controls. Similarly, patient survival was higher for <2‐year living‐donor recipients for posttransplant period >12 months (aHR: 0.21; 95% CI: 0.06–0.73; p =.01). The 5‐year dialysis‐free survival was higher for <2‐year deceased‐ (difference: 0.59 years; 95% CI: 0.23–0.93) and living‐donor (difference: 1.84 years; 95% CI: 1.31–2.25) recipients. Conclusion: Kidney transplantation in children <2 years of age is associated with improved patient survival and reduced dialysis exposure compared with remaining on the waitlist until ≥2 years. [ABSTRACT FROM AUTHOR]

Estimating causal effects from randomized controlled trials is often complicated due to participant noncompliance to randomized treatment. Although there are a variety of methods to estimate causal effects in the presence of noncompliance, they generally make the assumption that noncompliance is measured without error. This is frequently an untenable assumption, particularly when noncompliance is based on participant self-report. To overcome this issue, we treat compliance as an unobserved variable and show how to estimate the probability of compliance given a biomarker of treatment and the other observed data. We present inverse probability weighted estimators, regression-based estimators, and a doubly-robust augmented estimator that rely on the estimated probability of compliance rather than an indicator of compliance. We investigate the finite-sample properties of the estimators and their efficiency and robustness under correctly specified or misspecified models, and we apply the estimators to a recently completed trial of very low nicotine content cigarettes. [ABSTRACT FROM AUTHOR]

The difference in restricted mean survival times between two groups is a clinically relevant summary measure. With observational data, there may be imbalances in confounding variables between the two groups. One approach to account for such imbalances is estimating a covariate-adjusted restricted mean difference by modeling the covariate-adjusted survival distribution and then marginalizing over the covariate distribution. Because the estimator for the restricted mean difference is defined by the estimator for the covariate-adjusted survival distribution, it is natural to expect that a better estimator of the covariate-adjusted survival distribution is associated with a better estimator of the restricted mean difference. We therefore propose estimating restricted mean differences with stacked survival models. Stacked survival models estimate a weighted average of several survival models by minimizing predicted error. By including a range of parametric, semi-parametric, and non-parametric models, stacked survival models can robustly estimate a covariate-adjusted survival distribution and, therefore, the restricted mean treatment effect in a wide range of scenarios. We demonstrate through a simulation study that better performance of the covariate-adjusted survival distribution often leads to better mean squared error of the restricted mean difference although there are notable exceptions. In addition, we demonstrate that the proposed estimator can perform nearly as well as Cox regression when the proportional hazards assumption is satisfied and significantly better when proportional hazards is violated. Finally, the proposed estimator is illustrated with data from the United Network for Organ Sharing to evaluate post-lung transplant survival between large-volume and small-volume centers. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Obese transplant recipients (BMI ≥ 30 kg/m2) have decreased posttransplant patient and graft survival compared with their nonobese counterparts. At the same time, many prednisone‐related side effects (eg, new‐onset diabetes) are similar to those associated with obesity. Using SRTR data, we studied outcomes associated with prednisone‐free maintenance immunosuppression (rapid discontinuation of prednisone—RDP). Between January 1, 2000, and December 31, 2014, 44 635 first transplant recipients with BMI ≥ 30 kg/m2 had a first kidney transplant (28 176 DD; 16 459, LD); 12,994 (29%) were discharged from the hospital on a prednisone‐free protocol. We compared outcomes to those discharged on a protocol incorporating maintenance prednisone (intention‐to‐treat analysis). RDP‐treated obese first DD recipients had significantly better patient survival (HR, 0.88; CI, 0.81‐0.96) and graft survival (HR, 0.93; CI, 0.88‐0.99) compared with their counterparts on maintenance immunosuppression. Although not statistically significant, the same trends were seen for LD recipients. For both DD and LD recipients, there was no difference between groups for death‐censored graft survival, suggesting that the benefit of RDP was due to improved patient survival. Our findings suggest that kidney transplant recipients with BMI ≥ 30 kg/m2 benefit from a protocol that incorporates RDP. [ABSTRACT FROM AUTHOR]

Standardized methods for prescribing and monitoring exercise intensity are needed to advance exercise research in Alzheimer's disease ( AD). The purpose of this study was to evaluate the concurrent validity of a modified 1-10 Rating of Perceived Exertion ( RPE) scale against heart rate ( HR) in older adults with mild-to-moderate AD ( N = 8, age 77-87 years). RPE and HR were assessed every 5 min during each exercise session with 3,988 data pairs. Pearson and Spearman correlations and mixed models for correlated data were used for analysis. Results show the correlation between RPE and HR and between RPE and change in HR from resting was −.11 ( SE = .15) and −.31 ( SE = .17), respectively. The proportions of variance explained by RPE overall, RPE within participant, and RPE within session were only 4.0, 5.3, and 6.7%, respectively. We conclude that the modified 1-10 RPE scale did not show concurrent validity to HR, with large between-individual variability. [ABSTRACT FROM AUTHOR]

Temporal changes in kidney transplant outcomes for cystinosis are unknown. We used the SRTR to identify all kidney transplants performed for cystinosis in patients younger than 31 years between 1987 and 2017. We divided time into three equal eras (1987‐1997, 1998‐2007, and 2008‐2017) to assess changes in outcomes using Cox proportional and linear regression models. We examined 441 transplants in 362 patients. Age at ESRD progressively increased (12.1 vs 13.3 vs 13.4; P = .046). Eras 2 and 3 had lower risk of acute rejection (aHR 2 vs 1:0.45; P < .001) (aHR 3 vs 1:0.26; P < .001) and higher 5‐year mean GFR (difference 2 vs 1:9.2 mL/min/1.73 m2; P = .005) (difference 3 vs 1:12.9 mL/min/1.73 m2; P = .002) compared with era 1. Five‐year graft survival was similar across eras, but 5‐year patient survival was higher for era 2 (aHR: 0.25; P = .01). Seventy‐nine patients underwent retransplantation. Five‐year patient (94.2% vs 92.5%; P = .57) and graft survival (79.1% vs 74.1%; P = .52) were similar between primary and subsequent transplants. Age at ESRD, acute rejection, GFR at 5 years, and patient survival improved over time. Kidney retransplantation is associated with excellent outcomes in children and young adults with cystinosis. [ABSTRACT FROM AUTHOR]

Background: KT recipients have increased the risk of CVD. The incidence of post‐transplant CVEs among pediatric recipients has not been well‐characterized. Patients and Methods: Between 1963 and 2015, 884 pediatric (age: 0‐17 years old) recipients received 1058 KTs at our institution. The cumulative incidence of CVEs was analyzed. Statistical models were used to estimate risk factors for developing post‐transplant CVEs. Results: Overall median patient survival was 33 years (IQR: 18.7‐47). A total of 362 CVEs occurred in 161 (18.3%) patients at a median age of 20.5 years. Arrhythmias (18%) were most common. Cumulative risk of post‐transplant CVEs was 9% at 10 years, 17% at 20 years, 25% at 30 years, and 36% at 40 years. Development of post‐transplant CVEs was associated with increased mortality (HR 2.25 [95% CI 1.61‐3.14]); of those who developed a CVE and died, 22/51 (43.1%) died of CVD. Multivariable risk factors for post‐transplant CVEs included a history of pretransplant CVD (aHR 1.92 [1.18‐3.13] and graft failure (4.57 [3.13‐6.67]). Discussion: A pretransplant history of CVD and a failed graft are significant risk factors for the development of post‐transplant CVE. CVD increases the risk of post‐transplant death or graft loss. [ABSTRACT FROM AUTHOR]

Background: For many childhood cancers, survival is lower among non-Hispanic blacks and Hispanics in comparison with non-Hispanic whites, and this may be attributed to underlying socioeconomic factors. However, prior childhood cancer survival studies have not formally tested for mediation by socioeconomic status (SES). This study applied mediation methods to quantify the role of SES in racial/ethnic differences in childhood cancer survival.Methods: This study used population-based cancer survival data from the Surveillance, Epidemiology, and End Results 18 database for black, white, and Hispanic children who had been diagnosed at the ages of 0 to 19 years in 2000-2011 (n = 31,866). Black-white and Hispanic-white mortality hazard ratios and 95% confidence intervals, adjusted for age, sex, and stage at diagnosis, were estimated. The inverse odds weighting method was used to test for mediation by SES, which was measured with a validated census-tract composite index.Results: Whites had a significant survival advantage over blacks and Hispanics for several childhood cancers. SES significantly mediated the race/ethnicity-survival association for acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, and non-Hodgkin lymphoma; SES reduced the original association between race/ethnicity and survival by 44%, 28%, 49%, and 34%, respectively, for blacks versus whites and by 31%, 73%, 48%, and 28%, respectively, for Hispanics versus whites ((log hazard ratio total effect - log hazard ratio direct effect)/log hazard ratio total effect).Conclusions: SES significantly mediates racial/ethnic childhood cancer survival disparities for several cancers. However, the proportion of the total race/ethnicity-survival association explained by SES varies between black-white and Hispanic-white comparisons for some cancers, and this suggests that mediation by other factors differs across groups. [ABSTRACT FROM AUTHOR]

Abstract: With increasing organ demand, living kidney donation from older donors (>60‐years‐old) has become more common. Between 1975 and 2014, 3752 donor nephrectomies (DN) were performed at University of Minnesota; 167 (4.5%) were >60‐years‐old Short‐ and long‐term outcomes were compared between contemporaneous >60‐years‐old and <60‐years‐old donors. On univariate analysis, >60‐years‐old were more likely to have had prior abdominal surgery and hypertension; and less likely to smoke. Baseline estimated glomerular filtration rate (eGFR) was lower in >60‐years‐old (80 ± 16 vs 101 ± 26 mL/min/1.73 m2; P < .001). Intraoperative and postoperative complications were similar, except a higher prevalence of <30 day ileus (3% vs 7%; P = .021) and longer postoperative length of stay (LOS) (4.2 vs 4.6 days; P = .005). On multivariate analysis, <30 day ileus and LOS continued to be significantly greater for >60‐years‐old After >20 years post‐DN, systolic blood pressure was significantly higher among >60‐years‐old (142 vs 125 mm Hg; P < .001) and HTN was diagnosed earlier (9 vs 14 years). After donation, eGFR was significantly lower for >60‐years‐old but slope of eGFR and rates of end‐stage renal disease (ESRD) were not significantly different >20 years post‐DN. Thus, kidney donation among carefully selected >60‐years‐old poses minimal perioperative risks and no added risk of long‐term ESRD. [ABSTRACT FROM AUTHOR]

Predicting an individual's risk of experiencing a future clinical outcome is a statistical task with important consequences for both practicing clinicians and public health experts. Modern observational databases such as electronic health records provide an alternative to the longitudinal cohort studies traditionally used to construct risk models, bringing with them both opportunities and challenges. Large sample sizes and detailed covariate histories enable the use of sophisticated machine learning techniques to uncover complex associations and interactions, but observational databases are often 'messy', with high levels of missing data and incomplete patient follow-up. In this paper, we propose an adaptation of the well-known Naive Bayes machine learning approach to time-to-event outcomes subject to censoring. We compare the predictive performance of our method with the Cox proportional hazards model which is commonly used for risk prediction in healthcare populations, and illustrate its application to prediction of cardiovascular risk using an electronic health record dataset from a large Midwest integrated healthcare system. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Kidney transplantation entails well‐coordinated complex care delivery. Patient‐provider cultural and linguistic discordance can lead to healthcare disparities. We analyzed kidney transplantation outcomes among our institution's Hmong recipients using a retrospective cohort study. From 1995 to 2015, 2164 adult (age ≥18) recipients underwent kidney transplantation at our institution; 78 self‐identified as Hmong. Survival rates were analyzed and compared to Caucasian recipients (n = 2086). Fifty (64.1%) Hmong recipients consistently requested interpreters. Mean follow‐up was 9.8 years for both groups. Hmong recipients (N = 78) were on average younger at transplant (45.7 vs 49.7 years; P = 0.02), more likely to be female (56% vs 38%; P = 0.001), and had higher gravidity (5.0 vs 1.9 births; P < 0.001). There were 13 (16.7%) Hmong living donor recipients, who were younger (32.8 vs 42.9 years; P = 0.006) at transplant compared to Caucasians (1429, 68.5%). Hmong 1‐ and 5‐year patient survival was 100%; Caucasians, 97.1% and 88% (P < 0.001). Hmong 1‐ and 5‐year graft survival was 98.7% and 84.9%; Caucasians 94.8% and 80.9% (P = 0.013). One‐ and 5‐year rejection‐free survival showed no difference (88.9% vs 82.4%; 86.7% vs 83.4%, P = 0.996). Despite cultural and linguistic differences between Hmong recipients and providers, we found no evidence of inferiority in KT outcomes in the Hmong population. [ABSTRACT FROM AUTHOR]