SummaryBackground: For the statistical analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data, compartment models are a commonly used tool. By these models, the observed uptake of contrast agent in some tissue over time is linked to physiologic properties like capillary permeability and blood flow. Up to now, models of different complexity have been used, and it is still unclear which model should be used in which situation. In previous studies, it has been found that for DCE-MRI data, the number of compartments differs for different types of tissue, and that in cancerous tissue, it might actually differ over a region of voxels of one DCE-MR image. Objectives: To find the appropriate number of compartments and estimate the parameters of a regression model for each voxel in an DCE-MR image. With that, tumors in an DCE-MR image can be located, and for example therapy success can be assessed. Methods:The observed uptake of contrast agent in a voxel of an image of some tissue is described by a concentration time curve. This curve can be modeled using a nonlinear regression model. We present a boosting approach with nonlinear regression as base procedure, which allows us to estimate the number of compartments and the related parameters for each voxel of an DCE-MR image. In addition, a spatially regularized version of this approach is proposed. Results: With the proposed approach, the number of compartments -and with that the complexity of the model -per voxel is not fixed but data-driven, which allows us to fit models of adequate complexity to the concentration time curves of all voxels. The parameters of the model remain nevertheless interpretable because of the underlying compartment model. Conclusions:The proposed boosting approaches outperform all competing methods considered in this paper regarding the correct localization of tumors in DCE-MR images as well as the spatial homogeneity of the estimated number of compartments across the image, and the definition of the tumor edge.
Human protein biomarker discovery relies heavily on pre-clinical models, in particular established cell lines and patient-derived xenografts, but confirmation studies in primary tissue are essential to demonstrate clinical relevance. We describe in this study the process that was followed to clinically translate a 5-protein response signature predictive for the activity of an anti-HER3 monoclonal antibody (lumretuzumab) originally measured in fresh frozen xenograft tissue. We detail the development, qualification, and validation of the multiplexed targeted mass spectrometry assay used to assess the signature performance in formalin-fixed, paraffin-embedded human clinical samples collected in a phase Ib trial designed to evaluate lumretuzumab in patients with metastatic breast cancer. We believe that the strategy delineated here provides a path forward to avoid the time- and cost-consuming step of having to develop immunological reagents against unproven targets. We expect that mass spectrometry-based platforms may become part of a rational process to rapidly test and qualify large number of candidate biomarkers to identify the few that stand a chance for further development and validation.
Abstract:The binding behavior of molecules in nuclei of living cells can be studied through the analysis of images from fluorescence recovery after photobleaching experiments. However, there is still a lack of methodology for the statistical evaluation of FRAP data, especially for the joint analysis of multiple dynamic images. We propose a hierarchical Bayesian nonlinear model with mixed-effect priors based on local compartment models in order to obtain joint parameter estimates for all nuclei as well as to account for the heterogeneity of the nuclei population. We apply our method to a series of FRAP experiments of DNA methyltransferase 1 tagged to green fluorescent protein expressed in a somatic mouse cell line and compare the results to the application of three different fixed-effects models to the same series of FRAP experiments. With the proposed model, we get estimates of the off-rates of the interactions of the molecules under study together with credible intervals, and additionally gain information about the variability between nuclei. The proposed model is superior to and more robust than the tested fixedeffects models. Therefore, it can be used for the joint analysis of data from FRAP experiments on various similar nuclei.
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