Understanding the predictive value of continuous markers for censored survival data using a likelihood ratio approach

Abstract Background The likelihood ratio function (LR), the ratio of conditional probabilities of obtaining a specific marker value among those with the event of interest over those without, provides an easily interpretable way to quantify the update of the risk prediction due to the knowledge of the marker value. The LR has been explored for both binary and continuous markers for binary events (e.g., diseased or not), however the use of the LR in censored data has not been fully explored. Methods We extend the concept of LR to a time-dependent LR (TD-LR) for survival outcomes that are subject to censoring. Estimation for the TD-LR is done using Kaplan-Meier estimation and a univariate Cox proportional hazards (PH) model. A “scale invariant” approach based on marker quantiles is provided to allow comparison of predictive values between markers with different scales. Relationships to time-dependent receiver-operator characteristic (ROC) curves, area under the curve (AUC), and optimal cut-off values are considered. Results The proposed methods were applied to data from a bladder cancer clinical trial to determine whether the neutrophil-to-lymphocyte ratio (NLR) is a valuable biomarker for predicting overall survival following surgery or combined chemotherapy and surgery. The TD-LR method yielded results consistent with the original findings while providing an easily interpretable three-dimensional surface display of how NLR related to the likelihood of event in the trial data. Conclusions The TD-LR provides a more nuanced understanding of the relationship between continuous markers and the likelihood of events in censored survival data. This method also allows more straightforward communication with a clinical audience through graphical presentation.https://deepblue.lib.umich.edu/bitstream/2027.42/149185/1/12874_2019_Article_721.pd

The Radiation Therapy Technology Evidence Matrix: a framework to visualize evidence development for innovations in radiation therapy

Clinical evidence is crucial in enabling the judicious adoption of technological innovations in radiation therapy (RT). Pharmaceutical evidence development frameworks are not useful for understanding how technical advances are maturing. In this paper, we introduce a new framework, the Radiation Therapy Technology Evidence Matrix (rtTEM), that helps visualize how the clinical evidence supporting new technologies is developing. The matrix is a unique 2D model based on the R-IDEAL clinical evaluation framework. It can be applied to clinical hypothesis testing trials, as well as publications reporting clinical treatment. We present the rtTEM and illustrate its application, using emerging and mature RT technologies as examples. The model breaks down the type of claim along the vertical axis and the strength of the evidence for that claim on the horizontal axis, both of which are inherent in clinical hypothesis testing. This simplified view allows for stakeholders to understand where the evidence is and where it is heading. Ultimately, the value of an innovation is typically demonstrated through superiority studies, which we have divided into three key categories – administrative, toxicity and control, to enable more detailed visibility of evidence development in that claim area. We propose the rtTEM can be used to track evidence development for new interventions in RT. We believe it will enable researchers and sponsors to identify gaps in evidence and to further direct evidence development. Thus, by highlighting evidence looked for by key policy decision makers, the rtTEM will support wider, timely patient access to high value technological advances

Polymerization-based signal amplification for paper-based immunoassays

Diagnostic tests in resource-limited settings require technologies that are affordable and easy to use with minimal infrastructure. Colorimetric detection methods that produce results that are readable by eye, without reliance on specialized and expensive equipment, have great utility in these settings. We report a colorimetric method that integrates a paper-based immunoassay with a rapid, visible-light-induced polymerization to provide high visual contrast between a positive and a negative result. Using Plasmodium falciparum histidine-rich protein 2 as an example, we demonstrate that this method allows visual detection of proteins in complex matrices such as human serum and provides quantitative information regarding analyte levels when combined with cellphone-based imaging. It also allows the user to decouple the capture of analyte from signal amplification and visualization steps.Bill & Melinda Gates Foundation (Award 51308)United States. Defense Advanced Research Projects Agency (HR0011-12-2-0010)National Science Foundation (U.S.). Graduate Research FellowshipBurroughs Wellcome Fund (Career Award at the Scientific Interface

Broadly Available Imaging Devices Enable High-Quality Low-Cost Photometry

This paper demonstrates that, for applications in resource-limited environments, expensive microplate spectrophotometers that are used in many central laboratories for parallel measurement of absorbance of samples can be replaced by photometers based on inexpensive and ubiquitous, consumer electronic devices (e.g., scanners and cell-phone cameras). Two devices, (i) a flatbed scanner operating in transmittance mode and (ii) a camera-based photometer (constructed from a cell phone camera, a planar light source, and a cardboard box), demonstrate the concept. These devices illuminate samples in microtiter plates from one side and use the RGB-based imaging sensors of the scanner/camera to measure the light transmitted to the other side. The broadband absorbance of samples (RGB-resolved absorbance) can be calculated using the RGB color values of only three pixels per microwell. Rigorous theoretical analysis establishes a well-defined relationship between the absorbance spectrum of a sample and its corresponding RGB-resolved absorbance. The linearity and precision of measurements performed with these low-cost photometers on different dyes, which absorb across the range of the visible spectrum, and chromogenic products of assays (e.g., enzymatic, ELISA) demonstrate that these low-cost photometers can be used reliably in a broad range of chemical and biochemical analyses. The ability to perform accurate measurements of absorbance on liquid samples, in parallel and at low cost, would enable testing, typically reserved for well-equipped clinics and laboratories, to be performed in circumstances where resources and expertise are limited.Chemistry and Chemical Biolog

Comparative Analysis of 5-Year Clinical Outcomes and Patterns of Failure of Proton Beam Therapy Versus Intensity Modulated Radiation therapy for Prostate Cancer in the Postoperative Setting

Purpose: Although proton beam therapy (PBT) is a rapidly expanding modality to treat prostate cancer compared with intensity modulated radiation therapy (IMRT), data comparing disease control outcomes and patterns of failure in the postprostatectomy setting remain substantially limited. Methods and Materials: All patients who underwent postoperative IMRT or PBT to the prostate bed only at a single institution were included (2009-2017). Endpoints included biochemical failure (BF; using institutional and recent cooperative group trial definitions), local failure (LF), regional failure (RF), distant failure (DF), and all-cause mortality. A case-matched cohort analysis was performed using 3-to-1 nearest-neighbor matching; multivariable Cox proportional hazards modeling (MVA) estimated hazard ratios for disease-related outcomes by treatment modality. Results: Of 295 men, 260 were matched (n = 65 PBT, 195 IMRT); after matching, only age at diagnosis (P .05). RT modality was not significantly associated with BF on MVA using institutional or cooperative group definitions (all P > .05), nor with LF (P = .82), RF (P = .11), DF (P = .36), or all-cause mortality (P = .69). Patterns of failure were qualitatively similar between cohorts (DF: bone, retroperitoneal nodes, lung). Conclusions: In this single institution, case-matched analysis, PBT yielded similar long-term disease-related outcomes and patterns of failure to IMRT in the postprostatectomy setting. (C) 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved

Long-term Clinical Outcomes in Favorable Risk Prostate Cancer Patients Receiving Proton Beam Therapy

PURPOSE: Long-term data regarding the disease control outcomes of proton beam therapy (PBT) for patients with favorable risk intact prostate cancer (PC) are limited. Herein, we report our institution's long-term disease control outcomes in PC patients with clinically localized disease who received PBT as primary treatment. METHODS: One hundred sixty-six favorable risk PC patients who received definitive PBT to the prostate gland at our institution from 2010 to 2012 were retrospectively assessed. The outcomes studied were biochemical failure-free survival (BFFS), biochemical failure, local failure, regional failure, distant failure, PC-specific survival, and overall survival. Patterns of failure were also analyzed. Multivariate Cox proportional hazards modeling was used to estimate independent predictors of BFFS. RESULTS: The median length of follow-up was 8.3 years (range, 1.2–10.5 years). The majority of patients had low-risk disease (58%, n = 96), with a median age of 64 years at the onset of treatment. Of 166 treated men, 13 (7.8%), 8 (4.8%), 2 (1.2%) patient(s) experienced biochemical failure, local failure, regional failure, respectively. Regional failure was seen in an obturator lymph node in 1 patient and the external iliac lymph nodes in the other. None of the patients experienced distant failure. There were 5 (3.0%) deaths, none of which were due to PC. The 5- and 8-year BFFS rate were 97% and 92%, respectively. None of the clinical disease characteristics or treatment-related factors assessed were associated with BFFS on multivariate Cox proportional hazards modeling (all P > .05). CONCLUSION: Disease control rates reported in our assessment of PBT were similar to those reported in previous clinically localized intact PC analyses, which used intensity-modulated radiotherapy, three-dimensional conformal radiotherapy, or radical prostatectomy as definitive therapy. In addition, BFFS rates were similar, if not improved, to previous PBT studies

Topological Interference Management With Transmitter Cooperation

Interference networks with no channel state information at the transmitter except for the knowledge of the connectivity graph have been recently studied under the topological interference management framework. In this paper, we consider a similar problem with topological knowledge but in a distributed broadcast channel setting, i.e., a network where transmitter cooperation is enabled. We show that the topological information can also be exploited in this case to strictly improve the degrees of freedom (DoF) as long as the network is not fully connected, which is a reasonable assumption in practice. Achievability schemes from graph theoretic and interference alignment perspectives are proposed. Together with outer bounds built upon generator sequence, the concept of compound channel settings, and the relation to index coding, we characterize the symmetric DoF for the so-called regular networks with constant number of interfering links, and identify the sufficient and/or necessary conditions for the arbitrary network topologies to achieve a certain amount of symmetric DoF