Clinical Validation of Novel Digital Measures: Statistical Methods for Reliability Evaluation

Background: Assessment of reliability is one of the key components of the validation process designed to demonstrate that a novel clinical measure assessed by a digital health technology tool is fit-for-purpose in clinical research, care, and decision-making. Reliability assessment contributes to characterization of the signal-to-noise ratio and measurement error and is the first indicator of potential usefulness of the proposed clinical measure. Summary: Methodologies for reliability analyses are scattered across literature on validation of PROs, wet biomarkers, etc., yet are equally useful for digital clinical measures. We review a general modeling framework and statistical metrics typically used for reliability assessments as part of the clinical validation. We also present methods for the assessment of agreement and measurement error, alongside modified approaches for categorical measures. We illustrate the discussed techniques using physical activity data from a wearable device with an accelerometer sensor collected in clinical trial participants. Key Messages: This paper provides statisticians and data scientists, involved in development and validation of novel digital clinical measures, an overview of the statistical methodologies and analytical tools for reliability assessment

Anticoagulation in pediatric cancer–associated venous thromboembolism:a subgroup analysis of EINSTEIN-Jr

Anticoagulant treatment of pediatric cancer–associated venous thromboembolism (VTE) has not been prospectively evaluated. Management of anticoagulation for cancer-associated VTE is often challenged by drug interactions and treatment interruptions. A total of 56 of the 500 children (11.2%) with VTE who participated in the recent EINSTEIN-Jr randomized study had cancer (hematologic malignancy, 64.3%, solid malignant tumor, 35.7%). Children were allocated to either therapeutic-dose bodyweight-adjusted oral rivaroxaban (n=40) or standard anticoagulation with heparins, with or without vitamin K antagonists (n=16) and received a median of 30 concomitant medications. Based on sparse blood sampling at steady-state, pharmacokinetic (PK) parameters of rivaroxaban were derived using population PK modeling. During the 3 months of treatment, no recurrent VTE or major bleeding occurred (95% confidence interval, 0.0%-6.4%), and 3-month repeat imaging showed complete or partial vein recanalization in 20 and 24 of 52 evaluable children (38.5% and 46.2%, respectively). Anticoagulant treatment was interrupted 70 times in 26 (46.4%) children because of thrombocytopenia, invasive procedures, or adverse events, for a mean individual period of 5.8 days. Anticoagulant therapy was resumed in therapeutic doses and was not associated with thrombotic or bleeding complications. Rivaroxaban exposures were within the adult exposure range and similar to those observed in children with VTE who did not have cancer-associated VTE. Rivaroxaban and standard anticoagulants appeared safe and efficacious and were associated with reduced clot burden in most children with cancer-associated VTE, including those who had anticoagulant treatment interruptions. Rivaroxaban exposures were within the adult exposure range despite significant polypharmacy use. This trial was registered at www.clinicaltrials.gov as #NCT02234843

Conditional Tests for Multivariate One-sided Hypotheses with Missing Data

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biostatistics & Computational Biology, 2018.Treatment comparisons in randomized clinical trials usually involve several outcomes. Sometimes it is of interest to determine whether there is a treatment-associated improvement in disease status based on multiple outcomes, particularly if a treatment is expected to have the same directional effect on all of the outcomes. This gives rise to a multivariate onesided hypothesis. Under the multivariate normality assumption, Perlman (1969) derived the likelihood-ratio test in the one-sample case; however, its null distribution depends on the unknown covariance matrix and it is biased. Wang and McDermott (1998) derived a conditional likelihood ratio test (CLRT), conditioning on a sufficient statistic for the covariance matrix, resulting in a uniformly more powerful test. Recently, in an unpublished manuscript, Wang extended the CLRT to the two-sample case. This thesis explores the operating characteristics of the two-sample CLRT. In addition, this thesis develops practical extensions of the test such as covariate adjustment, a two-sided version, and outcome specific inference. Since the problem of missing data is ubiquitous in practical applications involving repeated measurements in multiple outcomes, this thesis proposes an observed likelihood-based approach to incorporate such missing data with a missing at random (MAR) mechanism in the CLRT. This thesis also considers the case of comparison of multiple treatments with respect to multiple outcomes and suggests a conditional test based on a statistic suggested by Sasabuchi (2003) for comparing multiple outcomes in K (> 2) samples. Derivation of the conditional test is provided and a resampling method to calculate the p-value is illustrated based on Markov Chain Monte Carlo sampling

Application of Bayesian methods to accelerate rare disease drug development: scopes and hurdles

Abstract Background Design and analysis of clinical trials for rare and ultra-rare disease pose unique challenges to the practitioners. Meeting conventional power requirements is infeasible for diseases where sample sizes are inherently very small. Moreover, rare disease populations are generally heterogeneous and widely dispersed, which complicates study enrollment and design. Leveraging all available information in rare and ultra-rare disease trials can improve both drug development and informed decision-making processes. Main text Bayesian statistics provides a formal framework for combining all relevant information at all stages of the clinical trial, including trial design, execution, and analysis. This manuscript provides an overview of different Bayesian methods applicable to clinical trials in rare disease. We present real or hypothetical case studies that address the key needs of rare disease drug development highlighting several specific Bayesian examples of clinical trials. Advantages and hurdles of these approaches are discussed in detail. In addition, we emphasize the practical and regulatory aspects in the context of real-life applications. Conclusion The use of innovative trial designs such as master protocols and complex adaptive designs in conjunction with a Bayesian approach may help to reduce sample size, select the correct treatment and population, and accurately and reliably assess the treatment effect in the rare disease setting.http://deepblue.lib.umich.edu/bitstream/2027.42/173792/1/13023_2022_Article_2342.pd

Anticoagulation in pediatric cancer–associated venous thromboembolism: a subgroup analysis of EINSTEIN-Jr

Anticoagulant treatment of pediatric cancer–associated venous thromboembolism (VTE) has not been prospectively evaluated. Management of anticoagulation for cancer-associated VTE is often challenged by drug interactions and treatment interruptions. A total of 56 of the 500 children (11.2%) with VTE who participated in the recent EINSTEIN-Jr randomized study had cancer (hematologic malignancy, 64.3%, solid malignant tumor, 35.7%). Children were allocated to either therapeutic-dose bodyweight-adjusted oral rivaroxaban (n=40) or standard anticoagulation with heparins, with or without vitamin K antagonists (n=16) and received a median of 30 concomitant medications. Based on sparse blood sampling at steady-state, pharmacokinetic (PK) parameters of rivaroxaban were derived using population PK modeling. During the 3 months of treatment, no recurrent VTE or major bleeding occurred (95% confidence interval, 0.0%-6.4%), and 3-month repeat imaging showed complete or partial vein recanalization in 20 and 24 of 52 evaluable children (38.5% and 46.2%, respectively). Anticoagulant treatment was interrupted 70 times in 26 (46.4%) children because of thrombocytopenia, invasive procedures, or adverse events, for a mean individual period of 5.8 days. Anticoagulant therapy was resumed in therapeutic doses and was not associated with thrombotic or bleeding complications. Rivaroxaban exposures were within the adult exposure range and similar to those observed in children with VTE who did not have cancer-associated VTE. Rivaroxaban and standard anticoagulants appeared safe and efficacious and were associated with reduced clot burden in most children with cancer-associated VTE, including those who had anticoagulant treatment interruptions. Rivaroxaban exposures were within the adult exposure range despite significant polypharmacy use

Anticoagulation in pediatric cancer-associated venous thromboembolism: a subgroup analysis of EINSTEIN-Jr

Anticoagulant treatment of pediatric cancer-associated venous thromboembolism (VTE) has not been prospectively evaluated. Management of anticoagulation for cancer-associated VTE is often challenged by drug interactions and treatment interruptions. A total of 56 (11.2%) of the 500 children with VTE who participated in the recent EINSTEIN-Jr randomized study had cancer (hematologic malignancy (n=36 [64.3%]) or a solid malignant tumor (n=20 [35.7%]). Children were allocated to either therapeutic-dose bodyweight-adjusted oral rivaroxaban (n=40) or standard anticoagulation with heparins with or without vitamin K antagonists (n=16) and received a median of 30 concomitant medications. Based on sparse blood sampling at steady-state, rivaroxaban PK parameters were derived using population PK modeling. During 3 months of treatment, no recurrent VTE or major bleeding occurred (95% confidence interval, 0.0-6.4%) and repeat imaging at 3 months showed complete or partial vein recanalisation in 20 (38.5%) and 24 (46.2%) of 52 evaluable children. Anticoagulant treatment was interrupted 70 times in 26 (46.4%) children because of thrombocytopenia, invasive procedures or adverse events, for a mean individual period of 5.8 days. Anticoagulant therapy was resumed in therapeutic doses and was not associated with thrombotic or bleeding complications. Rivaroxaban exposures were within the adult exposure range and similar to those observed in children with VTE who did not have cancer-associated VTE. Anticoagulation with either rivaroxaban or heparins with or without vitamin K antagonists appeared safe and efficacious and was associated with reduced clot burden in most children with cancer-associated VTE, including those who had anticoagulant treatment interruptions. Rivaroxaban exposures were within the adult exposure range despite significant polypharmacy use. The study is registered to www.clinicaltrials.gov as NCT02234843

Safety and efficacy of anticoagulant therapy in pediatric catheter-related venous thrombosis (EINSTEIN-Jr CVC-VTE)

International audienc

Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.

BACKGROUND Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11-1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51-6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING Bayer AG and Janssen Research & Development

Probing the chiral magnetic wave in pPb and PbPb collisions at root S-NN=5.02 TeV using charge-dependent azimuthal anisotropies

Charge-dependent anisotropy Fourier coefficients (v(n)) of particle azimuthal distributions are measured in pPb and PbPb collisions at root S-NN = 5.02 TeV with the CMS detector at the LHC. The normalized difference in the second-order anisotropy coefficients (v(2)) between positively and negatively charged particles is found to depend linearly on the observed event charge asymmetry with comparable slopes for both pPb and PbPb collisions over a wide range of charged particle multiplicity. In PbPb, the third-order anisotropy coefficient v(3) shows a similar linear dependence with the same slope as seen for v(2). The observed similarities between the v(2) slopes for pPb and PbPb, as well as the similar slopes for v(2) and v(3) in PbPb, are compatible with expectations based on local charge conservation in the decay of clusters or resonances, and constitute a challenge to the hypothesis that, at LHC energies, the observed charge asymmetry dependence of v(2) in heavy ion collisions arises from a chiral magnetic wave.Peer reviewe

Polypyrrole and associated hybrid nanocomposites as chemiresistive gas sensors: A comprehensive review

The detection of toxic and flammable gases entwines a wide diversity of application purposes, such as medical diagnosis, food quality monitoring, environmental tracking, and so forth. In recent, polypyrrole (PPy) nanostructure and its hybrid composite have been emerged as an auspicious gas sensing element because of their unique physicochemical attributes. This review article demonstrates a comprehensive outlook of rapid progress in polypyrrole (PPy) and associated hybrid composite based chemiresistive gas sensors till now. Furthermore, the role of PPy nanostructures and organic or inorganic additives (CNT, graphene or its derivative, metal nanoparticle, metal oxides, metal sulfides) in PPy matrix towards improved gas sensing performance are discussed hereunder. The detailed and systematic discussion on the synthesis strategies, gas sensing principle of the PPy nanostructures, and its composites along with the development of sensor device configuration provide an in-depth understanding of the aforesaid topic to the readers. However, some relevant limitations of PPy and associated composites based gas sensor are addressed after investigating the thorough literature survey. Finally, this article will promote an advanced as well as focused direction to the readers for further development of PPy based high-performance gas sensing devices