Bayesian data integration and variable selection for pan‐cancer survival prediction using protein expression data

Accurate prognostic prediction using molecular information is a challenging area of research, which is essential to develop precision medicine. In this paper, we develop translational models to identify major actionable proteins that are associated with clinical outcomes, like the survival time of patients. There are considerable statistical and computational challenges due to the large dimension of the problems. Furthermore, data are available for different tumor types; hence data integration for various tumors is desirable. Having censored survival outcomes escalates one more level of complexity in the inferential procedure. We develop Bayesian hierarchical survival models, which accommodate all the challenges mentioned here. We use the hierarchical Bayesian accelerated failure time model for survival regression. Furthermore, we assume sparse horseshoe prior distribution for the regression coefficients to identify the major proteomic drivers. We borrow strength across tumor groups by introducing a correlation structure among the prior distributions. The proposed methods have been used to analyze data from the recently curated “The Cancer Proteome Atlas” (TCPA), which contains reverse‐phase protein arrays–based high‐quality protein expression data as well as detailed clinical annotation, including survival times. Our simulation and the TCPA data analysis illustrate the efficacy of the proposed integrative model, which links different tumors with the correlated prior structures.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154486/1/biom13132_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154486/2/biom13132.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154486/3/biom13132-sup-0003-supmat.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154486/4/biom13132-sup-0002-supplementary-v6-22Jul2019.pd

Habitat characterization and spatial distribution of Anopheles sp. mosquito larvae in Dar es Salaam (Tanzania) during an extended dry period

Introduction: By 2030, more than 50% of the African population will live in urban areas. Controlling malaria reduces the disease burden and further improves economic development. As a complement to treated nets and prompt access to treatment, measures targeted against the larval stage of Anopheles sp. mosquitoes are a promising strategy for urban areas. However, a precise knowledge of the geographic location and potentially of ecological characteristics of breeding sites is of major importance for such interventions. Methods: In total 151 km2 of central Dar es Salaam, the biggest city of Tanzania, were systematically searched for open mosquito breeding sites. Ecologic parameters, mosquito larvae density and geographic location were recorded for each site. Logistic regression analysis was used to determine the key ecological factors explaining the different densities of mosquito larvae. Results: A total of 405 potential open breeding sites were examined. Large drains, swamps and puddles were associated with no or low Anopheles sp. larvae density. The probability of Anopheles sp. larvae to be present was reduced when water was identified as turbid . Small breeding sites were more commonly colonized by Anopheles sp. larvae. Further, Anopheles gambiae s.l. larvae were found in highly organically polluted habitats. Conclusions: Clear ecological characteristics of the breeding requirements of Anopheles sp. larvae could not be identified in this setting. Hence, every stagnant open water body, including very polluted ones, have to be considered as potential malaria vector breeding sites. © 2005 Sattler et al; licensee BioMed Central Ltd

A Randomized, Placebo-Controlled, Double-Blind Trial of the Effect of Combined Therapy With Deferoxamine and Deferiprone on Myocardial Iron in Thalassemia Major Using Cardiovascular Magnetic Resonance

Background— Cardiac complications secondary to iron overload are the leading cause of death in β-thalassemia major. Approximately two thirds of patients maintained on the parenteral iron chelator deferoxamine have myocardial iron loading. The oral iron chelator deferiprone has been demonstrated to remove myocardial iron, and it has been proposed that in combination with deferoxamine it may have additional effect. Methods and Results— Myocardial iron loading was assessed with the use of myocardial T2* cardiovascular magnetic resonance in 167 patients with thalassemia major receiving standard maintenance chelation monotherapy with subcutaneous deferoxamine. Of these patients, 65 with mild to moderate myocardial iron loading (T2* 8 to 20 ms) entered the trial with continuation of subcutaneous deferoxamine and were randomized to receive additional oral placebo (deferoxamine group) or oral deferiprone 75 mg/kg per day (combined group). The primary end point was the change in myocardial T2* over 12 months. Secondary end points of endothelial function (flow-mediated dilatation of the brachial artery) and cardiac function were also measured with cardiovascular magnetic resonance. There were significant improvements in the combined treatment group compared with the deferoxamine group in myocardial T2* (ratio of change in geometric means 1.50 versus 1.24; P =0.02), absolute left ventricular ejection fraction (2.6% versus 0.6%; P =0.05), and absolute endothelial function (8.8% versus 3.3%; P =0.02). There was also a significantly greater improvement in serum ferritin in the combined group (−976 versus −233 μg/L; P <0.001). Conclusions— In comparison to the standard chelation monotherapy of deferoxamine, combination treatment with additional deferiprone reduced myocardial iron and improved the ejection fraction and endothelial function in thalassemia major patients with mild to moderate cardiac iron loading

Periodic orbit effects on conductance peak heights in a chaotic quantum dot

We study the effects of short-time classical dynamics on the distribution of Coulomb blockade peak heights in a chaotic quantum dot. The location of one or both leads relative to the short unstable orbits, as well as relative to the symmetry lines, can have large effects on the moments and on the head and tail of the conductance distribution. We study these effects analytically as a function of the stability exponent of the orbits involved, and also numerically using the stadium billiard as a model. The predicted behavior is robust, depending only on the short-time behavior of the many-body quantum system, and consequently insensitive to moderate-sized perturbations.Comment: 14 pages, including 6 figure

Methodology based on genetic heuristics for in-vivo characterizing the patient-specific biomechanical behavior of the breast tissues

[EN] This paper presents a novel methodology to in-vivo estimate the elastic constants of a constitutive model proposed to characterize the mechanical behavior of the breast tissues. An iterative search algorithm based on genetic heuristics was constructed to in-vivo estimate these parameters using only medical images, thus avoiding invasive measurements of the mechanical response of the breast tissues. For the first time, a combination of overlap and distance coefficients were used for the evaluation of the similar- ity between a deformed MRI of the breast and a simulation of that deformation. The methodology was validated using breast software phantoms for virtual clinical trials, compressed to mimic MRI-guided biopsies. The biomechanical model chosen to characterize the breast tissues was an anisotropic neo-Hookean hyperelastic model. Results from this analysis showed that the algorithm is able to find the elastic constants of the constitutive equations of the proposed model with a mean relative error of about 10%. Furthermore, the overlap between the reference deformation and the simulated deformation was of around 95% showing the good performance of the proposed methodology. This methodology can be easily extended to characterize the real biomechanical behavior of the breast tissues, which means a great novelty in the field of the simulation of the breast behavior for applications such as surgical planing, surgical guidance or cancer diagnosis. This reveals the impact and relevance of the presented work.This project has been funded by MECD (reference AP2009-2414) and US National Institutes of Health (R01 Grant #CA154444), and the US National Science Foundation (III Grant #0916690). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, and NSF. The authors of this manuscript have no conflict of interest with the presented workLago, MA.; Rupérez Moreno, MJ.; Martínez Martínez, F.; Martinez-Sanchis, S.; Bakic, P.; Monserrat, C. (2015). Methodology based on genetic heuristics for in-vivo characterizing the patient-specific biomechanical behavior of the breast tissues. Expert Systems with Applications. 42(21):7942-7950. https://doi.org/10.1016/j.eswa.2015.05.058S79427950422

Sum rules and energy scales in the high-temperature superconductor YBa2Cu3O6+x

The Ferrell-Glover-Tinkham (FGT) sum rule has been applied to the temperature dependence of the in-plane optical conductivity of optimally-doped YBa_2Cu_3O_{6.95} and underdoped YBa_2Cu_3O_{6.60}. Within the accuracy of the experiment, the sum rule is obeyed in both materials. However, the energy scale \omega_c required to recover the full strength of the superfluid \rho_s in the two materials is dramatically different; \omega_c \simeq 800 cm^{-1} in the optimally doped system (close to twice the maximum of the superconducting gap, 2\Delta_0), but \omega_c \gtrsim 5000 cm^{-1} in the underdoped system. In both materials, the normal-state scattering rate close to the critical temperature is small, \Gamma < 2\Delta_0, so that the materials are not in the dirty limit and the relevant energy scale for \rho_s in a BCS material should be twice the energy gap. The FGT sum rule in the optimally-doped material suggests that the majority of the spectral weight of the condensate comes from energies below 2\Delta_0, which is consistent with a BCS material in which the condensate originates from a Fermi liquid normal state. In the underdoped material the larger energy scale may be a result of the non-Fermi liquid nature of the normal state. The dramatically different energy scales suggest that the nature of the normal state creates specific conditions for observing the different aspects of what is presumably a central mechanism for superconductivity in these materials.Comment: RevTeX 4 file, 9 pages with 7 embedded eps figure

Striatal mRNA expression patterns underlying peak dose L-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat

L-DOPA is the primary pharmacological treatment for relief of the motor symptoms of Parkinson’s disease (PD). With prolonged treatment (⩾5 years) the majority of patients will develop abnormal involuntary movements as a result of L-DOPA treatment, known as L-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step toward developing treatments for this debilitating side effect. We used the 6-hydroxydopamine (6-OHDA) rat model of PD treated with a three-week dosing regimen of L-DOPA plus the dopa decarboxylase inhibitor benserazide (4 mg/kg and 7.5 mg/kg s.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, non-dyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60 min after L-DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expression observed between all three groups. In dyskinetic animals 129 genes were more highly expressed and 14 less highly expressed when compared with non-dyskinetic and untreated parkinsonian controls. In L-DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate L-DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence

Effects of dopamine D1 modulation of the anterior cingulate cortex in a fear conditioning procedure

The anterior cingulate cortex (AC) component of the medial prefrontal cortex (mPFC) has been implicated in attention and working memory as measured by trace conditioning. Since dopamine (DA) is a key modulator of mPFC function, the present study evaluated the role of DA receptor agents in rat AC, using trace fear conditioning. A conditioned stimulus (CS, noise) was followed by an unconditioned stimulus (US, shock) with or without a 10s trace interval interposed between these events in a between-subjects design. Conditioned suppression of drinking was assessed in response to presentation of the CS or an experimental background stimulus (flashing lights, previously presented for the duration of the conditioning session). The selective D1 agonist SKF81297 (0.05 µg/side) or D1 antagonist SCH23390 (0.5 µg/side) was administered by intra-cerebral microinfusion directly into AC. It was predicted that either of these manipulations should be sufficient to impair trace (but not delay) conditioning. Counter to expectation, there was no effect of DA D1 modulation on trace conditioning as measured by suppression to the noise CS. However, rats infused with SKF81297 acquired stronger conditioned suppression to the experimental background stimulus than those infused with SCH23390 or saline. Thus, the DA D1 agonist SKF81297 increased conditioned suppression to the contextual background light stimulus but was otherwise without effect on fear conditioning

Detector Description and Performance for the First Coincidence Observations between LIGO and GEO

For 17 days in August and September 2002, the LIGO and GEO interferometer gravitational wave detectors were operated in coincidence to produce their first data for scientific analysis. Although the detectors were still far from their design sensitivity levels, the data can be used to place better upper limits on the flux of gravitational waves incident on the earth than previous direct measurements. This paper describes the instruments and the data in some detail, as a companion to analysis papers based on the first data.Comment: 41 pages, 9 figures 17 Sept 03: author list amended, minor editorial change