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1.
BMC Med Res Methodol ; 21(1): 216, 2021 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-34657597

RESUMO

BACKGROUND: Risk prediction models for time-to-event outcomes play a vital role in personalized decision-making. A patient's biomarker values, such as medical lab results, are often measured over time but traditional prediction models ignore their longitudinal nature, using only baseline information. Dynamic prediction incorporates longitudinal information to produce updated survival predictions during follow-up. Existing methods for dynamic prediction include joint modeling, which often suffers from computational complexity and poor performance under misspecification, and landmarking, which has a straightforward implementation but typically relies on a proportional hazards model. Random survival forests (RSF), a machine learning algorithm for time-to-event outcomes, can capture complex relationships between the predictors and survival without requiring prior specification and has been shown to have superior predictive performance. METHODS: We propose an alternative approach for dynamic prediction using random survival forests in a landmarking framework. With a simulation study, we compared the predictive performance of our proposed method with Cox landmarking and joint modeling in situations where the proportional hazards assumption does not hold and the longitudinal marker(s) have a complex relationship with the survival outcome. We illustrated the use of the RSF landmark approach in two clinical applications to assess the performance of various RSF model building decisions and to demonstrate its use in obtaining dynamic predictions. RESULTS: In simulation studies, RSF landmarking outperformed joint modeling and Cox landmarking when a complex relationship between the survival and longitudinal marker processes was present. It was also useful in application when there were several predictors for which the clinical relevance was unknown and multiple longitudinal biomarkers were present. Individualized dynamic predictions can be obtained from this method and the variable importance metric is useful for examining the changing predictive power of variables over time. In addition, RSF landmarking is easily implementable in standard software and using suggested specifications requires less computation time than joint modeling. CONCLUSIONS: RSF landmarking is a nonparametric, machine learning alternative to current methods for obtaining dynamic predictions when there are complex or unknown relationships present. It requires little upfront decision-making and has comparable predictive performance and has preferable computational speed.


Assuntos
Algoritmos , Aprendizado de Máquina , Biomarcadores , Simulação por Computador , Humanos , Modelos de Riscos Proporcionais
2.
BMC Med Res Methodol ; 21(1): 104, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33992081

RESUMO

BACKGROUND: Tacrolimus is given post-kidney transplant to suppress the immune system, and the amount of drug in the body is measured frequently. Higher variability over time may be indicative of poor drug adherence, leading to more adverse events. It is important to account for the variation in Tacrolimus, not just the average change over time. METHODS: Using data from the University of Colorado, we compare methods of assessing how the variability in Tacrolimus influences the hazard of de novo Donor Specific Antibodies (dnDSA), an early warning sign of graft failure. We compare multiple joint models in terms of fit and predictive ability. We explain that the models that account for the individual-specific variability over time have the best predictive performance. These models allowed each patient to have an individual-specific random error term in the longitudinal Tacrolimus model, and linked this to the hazard of dnDSA model. RESULTS: The hazard for the variance and coefficient of variation (CV) loading parameter were greater than 1, indicating that higher variability of Tacrolimus had a higher hazard of dnDSA. Introducing the individual-specific variability improved the fit, leading to more accurate predictions about the individual-specific time-to-dnDSA. CONCLUSIONS: We showed that the individual's variability in Tacrolimus is an important metric in predicting long-term adverse events in kidney transplantation. This is an important step in personalizing the dosage of TAC post-transplant to improve outcomes post-transplant.


Assuntos
Rejeição de Enxerto , Isoanticorpos , Biomarcadores , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Imunossupressores/efeitos adversos , Estudos Retrospectivos , Tacrolimo/efeitos adversos
3.
Neurooncol Adv ; 2(1): vdaa103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33063010

RESUMO

BACKGROUND: The mitogen-activated protein kinases/extracelluar signal-regulated kinases pathway is involved in cell growth and proliferation, and mutations in BRAF have made it an oncogene of interest in pediatric cancer. Previous studies found that BRAF mutations as well as KIAA1549-BRAF fusions are common in intracranial low-grade gliomas (LGGs). Fewer studies have tested for the presence of these genetic changes in spinal LGGs. The aim of this study was to better understand the prevalence of BRAF and other genetic aberrations in spinal LGG. METHODS: We retrospectively analyzed 46 spinal gliomas from patients aged 1-25 years from Children's Hospital Colorado (CHCO) and The Hospital for Sick Children (SickKids). CHCO utilized a 67-gene panel that assessed BRAF and additionally screened for other possible genetic abnormalities of interest. At SickKids, BRAF V600E was assessed by droplet digital polymerase chain reaction and immunohistochemistry. BRAF fusions were detected by fluorescence in situ hybridization, reverse transcription polymerase chain reaction, or NanoString platform. Data were correlated with clinical information. RESULTS: Of 31 samples with complete fusion analysis, 13 (42%) harbored KIAA1549-BRAF. All 13 (100%) patients with confirmed KIAA1549-BRAF survived the entirety of the study period (median [interquartile range] follow-up time: 47 months [27-85 months]) and 15 (83.3%) fusion-negative patients survived (follow-up time: 37.5 months [19.8-69.5 months]). Other mutations of interest were also identified in this patient cohort including BRAF V600E , PTPN11, H3F3A, TP53, FGFR1, and CDKN2A deletion. CONCLUSION: KIAA1549-BRAF was seen in higher frequency than BRAF V600E or other genetic aberrations in pediatric spinal LGGs and experienced lower death rates compared to KIAA1549-BRAF negative patients, although this was not statistically significant.

4.
J Am Soc Echocardiogr ; 33(2): 218-225, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31836268

RESUMO

BACKGROUND: Right ventricular (RV) failure, a determinant of outcomes in pulmonary hypertension (PH), occurs when the right ventricle cannot compensate for increased afterload. The authors showed that RV stroke work (RVSW) can be estimated in children with PH as the product of stroke volume and RV pressure and is related to adverse outcomes. The aim of this study was to test the hypothesis that ventricular-vascular (VV) mismatch (high afterload and low RVSW) is associated with echocardiographic measures of RV performance and adverse outcomes. METHODS: Invasive hemodynamic data and concurrent echocardiograms were reviewed. Fifty subjects with PH were included. Four groups were created by dividing the patients using median RVSW and median pulmonary vascular resistance. For each group, tricuspid annular plane systolic excursion, fractional area change, myocardial performance index, and anterior RV wall thickness were determined. Both major (i.e., death) and minor (i.e., worsening World Health Organization class) clinical outcomes were tabulated. Groups were compared using the Kruskal-Wallis or Fisher exact test. RESULTS: Patients in the high pulmonary vascular resistance/low RVSW cohort (VV mismatch) had the worst RV dysfunction: median tricuspid annular plane systolic excursion, 0.8 cm (interquartile range, 0.7-0.8 cm; P = .0002); median fractional area change, 0.29% (interquartile range, 0.27%-0.30%; P = .004); median myocardial performance index, 0.622 (interquartile range, 0.548-0.789; P = .0004). This group had the highest incidence of adverse outcomes: major events in 40%, minor events in 80%, and syncope in 60%. CONCLUSION: VV mismatch in pediatric PH can be assessed using RVSW and pulmonary vascular resistance and is associated with RV performance and adverse events. RVSW increases in compensated high-afterload states and falls as the right ventricle fails to meet increased load; thus, VV matching status may be a sensitive predictor of outcomes in pediatric PH.


Assuntos
Ecocardiografia/métodos , Ventrículos do Coração/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Volume Sistólico/fisiologia , Resistência Vascular/fisiologia , Função Ventricular Direita/fisiologia , Adolescente , Cateterismo Cardíaco/métodos , Criança , Estudos Transversais , Feminino , Seguimentos , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Artéria Pulmonar/diagnóstico por imagem , Estudos Retrospectivos
5.
BMC Med Res Methodol ; 19(1): 130, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242848

RESUMO

BACKGROUND: Tacrolimus (TAC) is an immunosuppressant drug given to kidney transplant recipients post-transplant to prevent antibody formation and kidney rejection. The optimal therapeutic dose for TAC is poorly defined and therapy requires frequent monitoring of drug trough levels. Analyzing the association between TAC levels over time and the development of potentially harmful de novo donor specific antibodies (dnDSA) is complex because TAC levels are subject to measurement error and dnDSA is assessed at discrete times, so it is an interval censored time-to-event outcome. METHODS: Using data from the University of Colorado Transplant Center, we investigated the association between TAC and dnDSA using a shared random effects (intercept and slope) model with longitudinal and interval censored survival sub-models (JM) and compared it with the more traditional interval censored survival model with a time-varying covariate (TVC). We carried out simulations to compare bias, level and power for the association parameter in the TVC and JM under varying conditions of measurement error and interval censoring. In addition, using Markov Chain Monte Carlo (MCMC) methods allowed us to calculate clinically relevant quantities along with credible intervals (CrI). RESULTS: The shared random effects model was a better fit and showed both the average TAC and the slope of TAC were associated with risk of dnDSA. The simulation studies demonstrated that, in the presence of heavy interval censoring and high measurement error, the TVC survival model underestimates the association between the survival and longitudinal measurement and has inflated type I error and considerably less power to detect associations. CONCLUSIONS: To avoid underestimating associations, shared random effects models should be used in analyses of data with interval censoring and measurement error.


Assuntos
Formação de Anticorpos/efeitos dos fármacos , Rejeição de Enxerto/prevenção & controle , Transplante de Rim/métodos , Tacrolimo/administração & dosagem , Doadores de Tecidos , Adulto , Algoritmos , Formação de Anticorpos/imunologia , Feminino , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/administração & dosagem , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Modelos Teóricos , Método de Monte Carlo , Fatores de Tempo
6.
Telemed J E Health ; 25(11): 1040-1048, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30681398

RESUMO

Introduction: To improve access to care and engage adolescent transplant recipients for adherence-promoting interventions, innovative solutions utilizing technology are needed. Materials and Methods: This study describes the implementation of a five-session group intervention targeting medication adherence in adolescent transplant recipients through home-based telemedicine. Results: Seven videoconferencing groups were conducted with a total of 33 participants living a median of 57 miles away from their transplant medical center. The median coefficient of variation (CV) of tacrolimus (immunosuppression medication) decreased from 32.2% to 23.5% from the pregroup to postgroup phase. Analyses indicated that the group was acceptable and engaging for participants, as highlighted by one participant reporting, "I liked how me and the group members came together… it felt like a little family." Overall satisfaction with the group and with the technology was endorsed by 86%. The group intervention was generally feasible; however, there were technological difficulties reported by participants and the facilitator, particularly given the diversity of the home-based connections and equipment. Other adaptations helped improve recruitment, attendance, and participation. Discussion: Implementing a telehealth group can pose unique challenges, especially with a group of adolescent participants. Although nonsignificant, we observed a decrease in the median CV of tacrolimus, indicating that medication adherence generally improved after group intervention. Our experience facilitating these groups provides insights into strategies to optimize feasibility and the participant experience. Distance of participants from the hospital is an important consideration and provides a strong rationale for the need for telemedicine-enabled approaches. We explore and discuss the challenges to implementing a home-based group, suggest practical strategies and developmentally sensitive adjustments when working with adolescents, and propose strategies to prepare clinicians for obstacles that may present when implementing a telehealth group with youth.


Assuntos
Acessibilidade aos Serviços de Saúde/organização & administração , Adesão à Medicação/estatística & dados numéricos , Telemedicina/organização & administração , Transplantados , Comunicação por Videoconferência/organização & administração , Adolescente , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Imunossupressores/uso terapêutico , Masculino , Satisfação do Paciente , Tacrolimo/uso terapêutico
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