Integrating biological knowledge into variable selection : an empirical Bayes approach with an application in cancer biology

Background: An important question in the analysis of biochemical data is that of identifying subsets of molecular variables that may jointly influence a biological response. Statistical variable selection methods have been widely used for this purpose. In many settings, it may be important to incorporate ancillary biological information concerning the variables of interest. Pathway and network maps are one example of a source of such information. However, although ancillary information is increasingly available, it is not always clear how it should be used nor how it should be weighted in relation to primary data. Results: We put forward an approach in which biological knowledge is incorporated using informative prior distributions over variable subsets, with prior information selected and weighted in an automated, objective manner using an empirical Bayes formulation. We employ continuous, linear models with interaction terms and exploit biochemically-motivated sparsity constraints to permit exact inference. We show an example of priors for pathway- and network-based information and illustrate our proposed method on both synthetic response data and by an application to cancer drug response data. Comparisons are also made to alternative Bayesian and frequentist penalised-likelihood methods for incorporating network-based information. Conclusions: The empirical Bayes method proposed here can aid prior elicitation for Bayesian variable selection studies and help to guard against mis-specification of priors. Empirical Bayes, together with the proposed pathway-based priors, results in an approach with a competitive variable selection performance. In addition, the overall procedure is fast, deterministic, and has very few user-set parameters, yet is capable of capturing interplay between molecular players. The approach presented is general and readily applicable in any setting with multiple sources of biological prior knowledge

Current Trends in Cancer Support Within the Religious Community

Living with cancer is associated with significant psychological strain. The prevalence and severity of this distress varies according to the time, type, and stage of cancer, as well as other variables including treatment regimen, side effects, and prognosis. More often than not, these struggles are neglected as part of the traditional cancer care plan. Yet, if left unaddressed, emotional strain can add to the suffering caused by cancer by negatively affecting treatment compliance. Faith communities, such as churches, provide an ideal atmosphere to serve and support individuals battling cancer. However, research indicates that spiritual care is often a neglected component in cancer care. Therefore, the purpose of this investigation was to describe felt needs of current cancer patients, availability of psychological services within religious settings, and the capacity of pastors to provide emotional support to cancer patients. Our investigation showed that the majority of church leaders recognize this need and desire training in this particular area. Therefore, a need for an effective church-equipping program is evident and should be a priority of cancer care providers

Treatment of tumours with the combination of WR-2721 and cis-dichlorodiammineplatinum (II) or cyclophosphamide.

The ability of WR-2721 [S-2(3-aminopropylamino)ethyl-phosporothioic acid] to selectively protect the host against the toxic effects of multiple doses of cis-dichlorodiammineplatinum [cis-Pt] or cyclophosphamide [CY] has been studied in mice and rats bearing 3 different tumours. Selective protection against cis-Pt induced nephrotoxicity has been demonstrated under all conditions studied, with the extent of protection being inversely related to the size of the cis-Pt dose. For example, pre-treatment with 200 mg/kg of WR-2721 30 min before each weekly dose of 2 mg/kg of cis-Pt allows the administration of this cytotoxic agent for 3 times longer before nephrotoxic injury. In none of these studies was there tumour protection. The same pattern was observed with CY, but quantitation of the extent of marrow protection was not possible for the multiple treatment studies, due to the longer latent period between induced and observed death with this drug. We conclude, therefore, that for both of these drugs, selective protection of the kidney and marrow is not only maintained under conditions of multiple treatment, but actually enhanced due to the need for smaller doses of cytotoxic agents in these protocols

Radiation Induced Stress Relaxation in Silicone and Polyurethane Elastomers

Many different materials are used in the National Ignition Facility, NIF, located at Lawrence Livermore National Laboratory, LLNL. Some of these are exposed to significant doses of ionizing radiation. Two elastomers are of special interest because they are used in sealing applications with long expected lifetimes. These are LPU4, a polyurethane formulated at LLNL, and Dow Corning DC93-500, a silicone RTV elastomer. In 2004 a program to determine the impact of ionizing radiation on the stress relaxation and compression set characteristics of these two elastomers was undertaken. Since the materials are used in continuous compression and must reliably seal, the primary test utilized was a stress relaxation test. This test provides insight into the ability of a seal to remain functional in a static seal. The test determines how much residual force remains after a certain period of time under compression. The temperature and absorbed radiation dose can dramatically impact this property. In this study the only independent environmental variable studied is the effect of radiation at ambient temperatures. Two levels of radiation exposure were studied, 1 MRad, and 10 MRad. One of the independent test parameters is the compression deflection during storage and in this test the value used was 25%. The need for a compression retention mechanism ruled out radiation exposure in the compressed direction since the high atomic number materials for that device would block the radiation. Therefore, an annular ring was chosen for the specimen shape. The procedures are, as closely as possible, based on ASTM D 6147-97. Since the data is readily obtained at the end of the stress relaxation test, the samples were also evaluated for compression set. Compression set is the essentially permanent deformation incurred in a seal after the seal is compressed for some period of time and then unloaded. Though this is indicative of potential sealing reliability, it is not as direct an indicator of seal performance as is stress relaxation. Compression set does not yield any useable, quantified information but is an indicator of viscoelastic deformation with time. The needed thickness measurements were obtained both from the unloading curves and direct measurement in general accordance with ASTM D395-03. The radiation source for this testing was the Co60 gamma source located at Lawrence Livermore National Laboratory (LLNL). This source has an exposure vessel approximately 29.2cm (11.5-inch) tall with an inside diameter of 7.44cm (2.93-inch). Because of the geometry limits, cylindrical symmetry and limited volume, a standard stress relaxation test such as ASTM D 6147-97 could not be utilized and a modified test was developed. An additional constraint imposed by the vertical asymmetry of the radiation dose in the exposure chamber was a limited height with reasonably uniform radiation exposure. The specific dimensions and radiation characteristics of the test cell are in Appendix A

A robust prognostic signature for hormone-positive node-negative breast cancer

BACKGROUND: Systemic chemotherapy in the adjuvant setting can cure breast cancer in some patients that would otherwise recur with incurable, metastatic disease. However, since only a fraction of patients would have recurrence after surgery alone, the challenge is to stratify high-risk patients (who stand to benefit from systemic chemotherapy) from low-risk patients (who can safely be spared treatment related toxicities and costs). METHODS: We focus here on risk stratification in node-negative, ER-positive, HER2-negative breast cancer. We use a large database of publicly available microarray datasets to build a random forests classifier and develop a robust multi-gene mRNA transcription-based predictor of relapse free survival at 10 years, which we call the Random Forests Relapse Score (RFRS). Performance was assessed by internal cross-validation, multiple independent data sets, and comparison to existing algorithms using receiver-operating characteristic and Kaplan-Meier survival analysis. Internal redundancy of features was determined using k-means clustering to define optimal signatures with smaller numbers of primary genes, each with multiple alternates. RESULTS: Internal OOB cross-validation for the initial (full-gene-set) model on training data reported an ROC AUC of 0.704, which was comparable to or better than those reported previously or obtained by applying existing methods to our dataset. Three risk groups with probability cutoffs for low, intermediate, and high-risk were defined. Survival analysis determined a highly significant difference in relapse rate between these risk groups. Validation of the models against independent test datasets showed highly similar results. Smaller 17-gene and 8-gene optimized models were also developed with minimal reduction in performance. Furthermore, the signature was shown to be almost equally effective on both hormone-treated and untreated patients. CONCLUSIONS: RFRS allows flexibility in both the number and identity of genes utilized from thousands to as few as 17 or eight genes, each with multiple alternatives. The RFRS reports a probability score strongly correlated with risk of relapse. This score could therefore be used to assign systemic chemotherapy specifically to those high-risk patients most likely to benefit from further treatment

Graphitized Needle Cokes and Natural Graphites for Lithium Intercalation

This paper examined effects of heat treatment and milling (before or after heat treatment) on the (electrochemical) intercalating ability of needle petroleum coke; natural graphite particles are included for comparison. 1 tab, 4 figs, 7 refs

Integrated analysis of breast cancer cell lines reveals unique signaling pathways

Mapping of sub-networks in the EGFR-MAPK pathway in different breast cancer cell lines reveals that PAK1 may be a marker for sensitivity to MEK inhibitors

Systems biology via redescription and ontologies (I): finding phase changes with applications to malaria temporal data

Biological systems are complex and often composed of many subtly interacting components. Furthermore, such systems evolve through time and, as the underlying biology executes its genetic program, the relationships between components change and undergo dynamic reorganization. Characterizing these relationships precisely is a challenging task, but one that must be undertaken if we are to understand these systems in sufficient detail. One set of tools that may prove useful are the formal principles of model building and checking, which could allow the biologist to frame these inherently temporal questions in a sufficiently rigorous framework. In response to these challenges, GOALIE (Gene ontology algorithmic logic and information extractor) was developed and has been successfully employed in the analysis of high throughput biological data (e.g. time-course gene-expression microarray data and neural spike train recordings). The method has applications to a wide variety of temporal data, indeed any data for which there exist ontological descriptions. This paper describes the algorithms behind GOALIE and its use in the study of the Intraerythrocytic Developmental Cycle (IDC) of Plasmodium falciparum, the parasite responsible for a deadly form of chloroquine resistant malaria. We focus in particular on the problem of finding phase changes, times of reorganization of transcriptional control