public 01:14:52

Joshua Vogelstein : Consistent Graph Classification applied to Human Brain Connectome Data

  -   Mathematical Biology ( 190 Views )

Graphs are becoming a favorite mathematical object for representation of data. Yet, statistical pattern recognition has focused almost entirely on vector valued data in Euclidean space. Graphs, however, live in graph space, which is non-Euclidean. Thus, most inference techniques are not even defined for graph valued data. Previous work in the classification of graph-valued data typically follows one of two recipes. (1) Vectorize the adjacency matrices of the graphs, and apply standard machine learning techniques. (2) Compute some number of graph invariants (e.g., clustering coefficient, or degree distribution) for each graph, and then apply standard machine learning techniques. We follow a different recipe based in the probabilistic theory of pattern recognition. First, we define a joint graph-class model. Given this model, we derive classifiers which we prove are consistent; that is, they converge to the Bayes optimal classifier. Specifically, we build two consistent classifiers for graph valued data, a parametric and a non-parametric version. In a sense, these classifiers span the spectrum of complexity, the former is consistent for graphs sampled from relatively simple random graph distributions, the latter is consistent for graphs sampled from (nearly) any random graph distribution. Although both classifiers assume that all our graphs have labeled vertices, we generalize these results to also incorporate unlabeled graphs, as well as weighted and multigraphs. We apply these graph classifiers to human brain data. Specifically, using diffusion MRI, we can obtain large brain-graphs (10,000 vertices) for each subject, where vertices correspond to voxels. We then coarsen the graphs spatially to obtain smaller (70 vertex) graphs per subject. Using <50 subjects, we are able to achieve nearly 85% classification accuracy, with results interpretable to neurobiologists with regard to the brain regions of interest.

public 01:29:51

Franziska Michor : Evolutionary dynamics of cancer

  -   Mathematical Biology ( 132 Views )

Cancer emerges due to an evolutionary process in somatic tissue. The fundamental laws of evolution can best be formulated as exact mathematical equations. Therefore, the process of cancer initiation and progression is amenable to mathematical investigation. Of special importance are changes that occur early during malignant transformation because they may result in oncogene addiction and represent promising targets for therapeutic intervention. Here we describe a mathematical approach, called Retracing the Evolutionary Steps in Cancer (RESIC), to deduce the temporal sequence of genetic events during tumorigenesis from crosssectional genomic data of tumors at their fully transformed stage. When applied to a dataset of 70 advanced colorectal cancers, our algorithm accurately predicts the sequence of APC, KRAS, and TP53 mutations previously defined by analyzing tumors at different stages of colon cancer formation. We further validate the method with glioblastoma and leukemia sample data and then apply it to complex integrated genomics databases, finding that high-level EGFR amplification appears to be a late event in primary glioblastomas. RESIC represents the first evolutionary mathematical approach to identify the temporal sequence of mutations driving tumorigenesis and may be useful to guide the validation of candidate genes emerging from cancer genome surveys.

public 01:14:42

Hans Othmer : A hybrid model of tumor-stromal interactions in breast cancer

  -   Mathematical Biology ( 137 Views )

Ductal carcinoma in situ (DCIS) is an early stage non-invasive breast cancer that originates in the epithelial lining of the milk ducts, but it can evolve into comedo DCIS and ultimately, into the most common type of breast cancer, invasive ductal carcinoma. Understanding the progression and how to effectively intervene in it presents a major scientific challenge. The extracellular matrix surrounding a duct contains several types of cells and several types of growth factors that are known to individually affect tumor growth, but at present the complex biochemical and mechanical interactions of these stromal cells and growth factors with tumor cells is poorly understood. We will discuss a mathematical model that incorporates the cross-talk between stromal and tumor cells, and which can predict how perturbations of the local biochemical and mechanical state influence tumor evolution. We focus on the EGF and TGF-$\beta$ signaling pathways and show how up- or down-regulation of components in these pathways affects cell growth and proliferation, and describe a hybrid model for the interaction of cells with the tumor microenvironment. The analysis sheds light on the interactions between growth factors, mechanical properties of the ECM, and feedback signaling loops between stromal and tumor cells, and suggests how epigenetic changes in transformed cells affect tumor progression.

public 01:29:52

Badal Joshi : A Markov model for pole formation

  -   Mathematical Biology ( 125 Views )

public 53:20

Dean Bottino : Evaluating Strategies for Overcoming Rituximab (R) Resistance Using a Quantitative Systems Pharmacology (QSP) model of Antibody-Dependent Cell-mediated Cytotoxicity & Phagocytosis (ADCC & ADCP): An Academic/Industrial Collaboration

  -   Mathematical Biology ( 70 Views )

Despite the impressive performance of rituximab (R) containing regimens like R-CHOP in CD20+ Non-Hodgkin’s Lymphoma (NHL), 30-60% of R-naïve NHL patients are estimated to be resistant, and approximately 60% of those patients will not respond to subsequent single agent R treatment. Given that antibody dependent cell mediated cytotoxicity (ADCC) and phagocytosis (ADCP) are thought to be the major mechanisms of action of Rituximab, increasing the activation levels of natural killer (NK) and macrophage (MP) cells may be one strategy for overcoming R resistance.

During (and after) the Fields Institute Industrial Problem Solving Workshop in August 2019, academic participants and industry mentors developed and calibrated to literature data a quantitative systems pharmacology (QSP) model of ADCC/ADCP to interrogate which mechanisms of R resistance could be overcome by increased NK or MP activation, and how much effector cell activation would be required to overcome a given degree and mechanism of R resistance.

This work was motivated by a real-world pharmaceutical drug development question, and the academic-industry interactions during and after the workshop resulted in sharknado plots as well as a published QSP model (presented at American Association of Cancer Research Annual Meeting, 2021) that was able to address some of the key questions around overcoming R resistance. The published model was then incorporated into an in-house QSP model supporting the development of a Takeda investigational drug which is being developed to restore R sensitivity in an R-resistant patient population.

public 01:14:48

Steven Baer : Multiscale Modeling of Neural Subcircuits and Feedback Mechanisms in the Outer Plexiform Layer of the Retina

  -   Mathematical Biology ( 140 Views )

Visual processing begins in the outer plexiform layer of the retina, where
bipolar, horizontal, and photoreceptor cells interact. In vertebrates, the
onset of dim backgrounds can enhance small spot flicker responses of
retinal horizontal cells. This flicker response is called background-
induced flicker enhancement. The underlying mechanism for the feedback
is unclear but competing hypotheses have been proposed. One is the GABA
hypothesis, which states that the inhibitory neurotransmitter GABA,
released from horizontal cells, mediates the feedback by blocking calcium
channels. Another is the ephaptic hypothesis, which contends that calcium
entry is regulated by changes in the electrical potential within the
intersynaptic space between cones and horizontal cells. In this study, a
continuum spine model of cone-horizontal cell synaptic circuitry is
formulated. The model captures two spatial scales - the scale of an
individual synapse and the scale of the receptive field involving hundreds
to thousands of synapses. We show that the ephaptic mechanism produces
reasonable qualitative agreement with the temporal dynamics exhibited by
flicker enhancement experiments. We find that although GABA produces
enhancement, this mechanism alone is insufficient to reproduce the
experimental results. We view this multiscale continuum approach as a
first step in formulating a multi-layer mathematical model of retinal
circuitry, which would include the other ‘brain nuclei’ within the retina:
the inner plexiform layer where bipolar, amacrine, interplexiform, and
ganglion cells interact.