Use of Modeling and Simulation in the Design and Conduct of Pediatric Clinical Trials and the Optimization of Individualized Dosing Regimens

Mathematical models of drug action and disease progression can inform pediatric pharmacotherapy. In this tutorial, we explore the key issues that differentiate pediatric from adult pharmacokinetic (PK) / pharmacodynamic (PD) studies, describe methods to calculate the number of participants to be enrolled and the optimal times at which blood samples should be collected, and therapeutic drug monitoring methods for individualizing pharmacotherapy. The development of pediatric‐specific drug dosing dashboards is also highlighted, with an emphasis on clinical‐relevance and ease of use

The use of repeated blood pressure measures for cardiovascular risk prediction: a comparison of statistical models in the ARIC study.

Many prediction models have been developed for the risk assessment and the prevention of cardiovascular disease in primary care. Recent efforts have focused on improving the accuracy of these prediction models by adding novel biomarkers to a common set of baseline risk predictors. Few have considered incorporating repeated measures of the common risk predictors. Through application to the Atherosclerosis Risk in Communities study and simulations, we compare models that use simple summary measures of the repeat information on systolic blood pressure, such as (i) baseline only; (ii) last observation carried forward; and (iii) cumulative mean, against more complex methods that model the repeat information using (iv) ordinary regression calibration; (v) risk-set regression calibration; and (vi) joint longitudinal and survival models. In comparison with the baseline-only model, we observed modest improvements in discrimination and calibration using the cumulative mean of systolic blood pressure, but little further improvement from any of the complex methods. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.J.K.B. was supported by the Medical Research Council grant numbers G0902100 and MR/K014811/1. This work was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834) and European Commission Framework Programme 7 (HEALTH-F2-2012-279233). The ARIC study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C).This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1002/sim.714

The North American Freshwater Turtle Research Group (NAFTRG): An undergraduate research experience (URE) and citizen scientist project

Researchers today understand the importance of incorporating undergraduate research experiences (URE) and citizen-science methods into data collection and long-term research projects. The North American Freshwater Turtle Research Group (NAFTRG) is an example of a project in which both methods are implemented. The NAFTRG conducts long-term studies on turtle populations in seven state park springs in Florida and the largest freshwater spring in Texas. Although the study began as an undergraduate biology class, it has expanded throughout the years into a study that many parks and researchers rely upon for important data on turtle populations and for information that helps manage the stability of ecosystems. Through the use of UREs, the research investigators are enabling undergraduates to gain valuable research experiences while maintaining a volunteer base that has a vested interest in the study itself. Students from Pennsylvania State University, University of North Florida, Peninsula College, Freed-Hardeman University, and Western Washington University have chosen to participate in the study. Many of these students have volunteered additional time and efforts during subsequent research trips. A project of this nature enables students to see the importance of ecosystem awareness. Through the use of citizen science, investigators can form a large volunteer base while incorporating sophisticated ecological methodologies and furthering coonservation efforts. Many participating citizen scientists have jobs unrelated to the sciences; they volunteer their time because they understand the importance of the group’s objectives and are willing to support them with their time and energy. Our current volunteer base receives further support from local zoos, aquariums, amusement parks, and the public. Based on standardized values for volunteer work, citizen scientists and donations from governmental and non-governmental organizations have contributed approximately one million dollars to this project. Citizen science is helping to bridge the gap between the general public and the scientific community by allowing the two to work together in monitoring, managing, maintaining, and understanding the ecological issues around us. &nbsp

Landmark Models for Optimizing the Use of Repeated Measurements of Risk Factors in Electronic Health Records to Predict Future Disease Risk.

The benefits of using electronic health records (EHRs) for disease risk screening and personalized health-care decisions are being increasingly recognized. Here we present a computationally feasible statistical approach with which to address the methodological challenges involved in utilizing historical repeat measures of multiple risk factors recorded in EHRs to systematically identify patients at high risk of future disease. The approach is principally based on a 2-stage dynamic landmark model. The first stage estimates current risk factor values from all available historical repeat risk factor measurements via landmark-age-specific multivariate linear mixed-effects models with correlated random intercepts, which account for sporadically recorded repeat measures, unobserved data, and measurement errors. The second stage predicts future disease risk from a sex-stratified Cox proportional hazards model, with estimated current risk factor values from the first stage. We exemplify these methods by developing and validating a dynamic 10-year cardiovascular disease risk prediction model using primary-care EHRs for age, diabetes status, hypertension treatment, smoking status, systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol in 41,373 persons from 10 primary-care practices in England and Wales contributing to The Health Improvement Network (1997-2016). Using cross-validation, the model was well-calibrated (Brier score = 0.041, 95% confidence interval: 0.039, 0.042) and had good discrimination (C-index = 0.768, 95% confidence interval: 0.759, 0.777)

Alert Networks of ICTs and Sources in Campus Emergencies

ABSTRACT This study contributes an understanding of how ICTs and varying information sources work together during emergency alerts. It builds on the prior work on campus active shooter events by examining an organization that used a range of ICTs including mobile devices, social media, organizational tools, and news media, to notify their stakeholders about an emergency. The study design used a survey to capture the responses from a random sample of over 1000 stakeholders-students, faculty, and staff-who were notified of an active shooter emergency. The findings from the first three notifications suggest that messages reaching the most stakeholders were (a) sent by official sources through ICTs like mobile phones; (b) official email communication, and (c) messages that included face-to-face communication. While 11 different ICTs were included in the study, mass media (i.e., television and radio), and social media (Twitter and Facebook) did not function substantially in the emergency alert process

Alert Networks of ICTs and Sources in Campus Emergencies

ABSTRACT This study contributes an understanding of how ICTs and varying information sources work together during emergency alerts. It builds on the prior work on campus active shooter events by examining an organization that used a range of ICTs including mobile devices, social media, organizational tools, and news media, to notify their stakeholders about an emergency. The study design used a survey to capture the responses from a random sample of over 1000 stakeholders-students, faculty, and staff-who were notified of an active shooter emergency. The findings from the first three notifications suggest that messages reaching the most stakeholders were (a) sent by official sources through ICTs like mobile phones; (b) official email communication, and (c) messages that included face-to-face communication. While 11 different ICTs were included in the study, mass media (i.e., television and radio), and social media (Twitter and Facebook) did not function substantially in the emergency alert process

Effect of early glycemic control on HbA1c tracking and development of vascular complications after 5 years of childhood onset type 1 diabetes: Systematic review and meta-analysis.

OBJECTIVE: A systematic review and meta-analysis was conducted to investigate if glycemic control measured by glycated hemoglobin (HbA1c) levels near diagnosis are predictive of future glycemic outcomes and vascular complications in childhood onset type 1 diabetes (T1D). METHODS: Evidence was gathered using electronic databases (MEDLINE, EMBASE, Web of Science, CINAHL, Scopus, and Cochrane Library up to February 2017) and snowballing techniques. Studies investigating the association between the exposure "early glycemic control" and main outcome: "tracking of early control" and secondary outcome: risk of future complications; in children and young people aged 0 to 19 years at baseline; were systematically double-reviewed, quality assessed, and outcome data extracted for synthesis and meta-analysis. FINDINGS: Five studies (N = 4227 participants) were eligible. HbA1c levels were sub-optimal throughout the study period but tended to stabilize in a "track" by 6 months after T1D diagnosis. The group with low HbA1c <53 mmol/mol (<7%) at baseline had lower long-term HbA1c levels than the higher HbA1c group. The estimated standardized mean difference between the sub groups showed a reduction of HbA1c levels on average by 1.6% (range -0.95% to -2.28%) from baseline. Only one study investigated the association between early glycemic control and development of vascular complications in childhood onset T1D. INTERPRETATIONS: Glycemic control after the first few months of childhood onset T1D, remains stable but sub-optimal for a decade. The low and high HbA1c levels at baseline seem to "track" in their respective tracks during the 10-year follow-up, however, the initial difference between groups narrows over time. PROSPERO: CRD42015024546 http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015024546

Evidence for Differential Viral Oncolytic Efficacy in an In Vitro Model of Epithelial Ovarian Cancer Metastasis

Epithelial ovarian cancer is unique among most carcinomas in that metastasis occurs by direct dissemination of malignant cells traversing throughout the intraperitoneal fluid. Accordingly, we test new therapeutic strategies using an in vitro three-dimensional spheroid suspension culture model that mimics key steps of this metastatic process. In the present study, we sought to uncover the differential oncolytic efficacy among three different viruses—Myxoma virus, double-deleted vaccinia virus, and Maraba virus—using three ovarian cancer cell lines in our metastasis model system. Herein, we demonstrate that Maraba virus effectively infects, replicates, and kills epithelial ovarian cancer (EOC) cells in proliferating adherent cells and with slightly slower kinetics in tumor spheroids. Myxoma virus and vaccinia viruses infect and kill adherent cells to a much lesser extent than Maraba virus, and their oncolytic potential is almost completely attenuated in spheroids. Myxoma virus and vaccinia are able to infect and spread throughout spheroids, but are blocked in the final stages of the lytic cycle, and oncolytic-mediated cell killing is reactivated upon spheroid reattachment. Alternatively, Maraba virus has a remarkably reduced ability to initially enter spheroid cells, yet rapidly infects and spreads throughout spheroids generating significant cell killing effects. We show that low-density lipoprotein receptor expression in ovarian cancer spheroids is reduced and this controls efficient Maraba virus binding and entry into infected cells. Taken together, these results are the first to implicate the potential impact of differential viral oncolytic properties at key steps of ovarian cancer metastasis

MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia

We identified mutations in the IL7Ra gene or in genes encoding the downstream signaling molecules JAK1, JAK3, STAT5B, N-RAS, K-RAS, NF1, AKT and PTEN in 49% of patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL). Strikingly, these mutations (except RAS/NF1) were mutually exclusive, suggesting that they each cause the aberrant activation of a common downstream target. Expressing these mutant signaling molecules—but not their wild-type counterparts—rendered Ba/F3 cells independent of IL3 by activating the RAS-MEK-ERK and PI3K-AKT pathways. Interestingly, cells expressing either IL7Ra or JAK mutants are sensitive to JAK inhibitors, but respond less robustly to inhibitors of the downstream RAS-MEK-ERK and PI3K-AKT-mTOR pathways, indicating that inhibiting only one downstream pathway is not sufficient. Here, we show that inhibiting both the MEK and PI3K-AKT pathways synergistically prevents the proliferation of BaF3 cells expressing mutant IL7Ra, JAK and RAS. Furthermore, combined inhibition of MEK and PI3K/AKT was cytotoxic to samples obtained from 6 out of 11 primary T-ALL patients, including 1 patient who had no mutations in the IL7R signaling pathway. Taken together, these results suggest that the potent cytotoxic effects of inhibiting both MEK and PI3K/AKT should be investigated further as a therapeutic option using leukemia xenograft models.Leukemia advance online publication, 13 May 2016; doi:10.1038/leu.2016.83

Measurements in two bases are sufficient for certifying high-dimensional entanglement

High-dimensional encoding of quantum information provides a promising method of transcending current limitations in quantum communication. One of the central challenges in the pursuit of such an approach is the certification of high-dimensional entanglement. In particular, it is desirable to do so without resorting to inefficient full state tomography. Here, we show how carefully constructed measurements in two bases (one of which is not orthonormal) can be used to faithfully and efficiently certify bipartite high-dimensional states and their entanglement for any physical platform. To showcase the practicality of this approach under realistic conditions, we put it to the test for photons entangled in their orbital angular momentum. In our experimental setup, we are able to verify 9-dimensional entanglement for a pair of photons on a 11-dimensional subspace each, at present the highest amount certified without any assumptions on the state.Comment: 11+14 pages, 2+7 figure