Estimation of variance components, heritability and the ridge penalty in high-dimensional generalized linear models

For high-dimensional linear regression models, we review and compare several estimators of variances τ2 and σ2 of the random slopes and errors, respectively. These variances relate directly to ridge regression penalty λ and heritability index h2, often used in genetics. Several estimators of these, either based on cross-validation (CV) or maximum marginal likelihood (MML), are also discussed. The comparisons include several cases of the high-dimensional covariate matrix such as multi-collinear covariates and data-derived ones. Moreover, we study robustness against model misspecifications such as sparse instead of dense effects and non-Gaussian errors. An example on weight gain data with genomic covariates confirms the good performance of MML compared to CV. Several extensions are presented. First, to the high-dimensional linear mixed effects model, with REML as an alternative to MML. Second, to the conjugate Bayesian setting, shown to be a good alternative. Third, and most prominently, to generalized linear models for which we derive a computationally efficient MML estimator by re-writing the marginal likelihood as an n-dimensional integral. For Poisson and Binomial ridge regression, we demonstrate the superior accuracy of the resulting MML estimator of λ as compared to CV. Software is provided to enable reproduction of all results.Gwenaël Leday was supported by the Medical Research Council, grant number MR/M004421

Genomic aberrations relate early and advanced stage ovarian cancer

Background Because of the distinct clinical presentation of early and advanced stage ovarian cancer, we aim to clarify whether these disease entities are solely separated by time of diagnosis or whether they arise from distinct molecular events. Methods Sixteen early and sixteen advanced stage ovarian carcinomas, matched for histological subtype and differentiation grade, were included. Genomic aberrations were compared for each early and advanced stage ovarian cancer by array comparative genomic hybridization. To study how the aberrations correlate to the clinical characteristics of the tumors we clustered tumors based on the genomic aberrations. Results The genomic aberration patterns in advanced stage cancer equalled those in early stage, but were more frequent in advanced stage (p=0.012). Unsupervised clustering based on genomic aberrations yielded two clusters that significantly discriminated early from advanced stage (p= 0.001), and that did differ significantly in survival (p= 0.002). These clusters however did give a more accurate prognosis than histological subtype or differentiation grade. Conclusion This study indicates that advanced stage ovarian cancer either progresses from early stage or from a common precursor lesion but that they do not arise from distinct carcinogenic molecular events. Furthermore, we show that array comparative genomic hybridization has the potential to identify clinically distinct patients

Unexpected features of branched flow through high-mobility two-dimensional electron gases

GaAs-based two-dimensional electron gases (2DEGs) show a wealth of remarkable electronic states, and serve as the basis for fast transistors, research on electrons in nanostructures, and prototypes of quantum-computing schemes. All these uses depend on the extremely low levels of disorder in GaAs 2DEGs, with low-temperature mean free paths ranging from microns to hundreds of microns. Here we study how disorder affects the spatial structure of electron transport by imaging electron flow in three different GaAs/AlGaAs 2DEGs, whose mobilities range over an order of magnitude. As expected, electrons flow along narrow branches that we find remain straight over a distance roughly proportional to the mean free path. We also observe two unanticipated phenomena in high-mobility samples. In our highest-mobility sample we observe an almost complete absence of sharp impurity or defect scattering, indicated by the complete suppression of quantum coherent interference fringes. Also, branched flow through the chaotic potential of a high-mobility sample remains stable to significant changes to the initial conditions of injected electrons.Comment: 22 pages, 4 figures, 1 tabl

Multiple putative oncogenes at the chromosome 20q amplicon contribute to colorectal adenoma to carcinoma progression

Objective: This study aimed to identify the oncogenes at 20q involved in colorectal adenoma to carcinoma progression by measuring the effect of 20q gain on mRNA expression of genes in this amplicon. Methods: Segmentation of DNA copy number changes on 20q was performed by array CGH (comparative genomic hybridisation) in 34 non-progressed colorectal adenomas, 41 progressed adenomas (ie, adenomas that present a focus of cancer) and 33 adenocarcinomas. Moreover, a robust analysis of altered expression of genes in these segments was performed by microarray analysis in 37 adenomas and 31 adenocarcinomas. Protein expression was evaluated by immunohistochemistry on tissue microarrays. Results: The genes C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5, mapping at 20q, were significantly overexpressed in carcinomas compared with adenomas as a consequence of copy number gain of 20q. Conclusion: This approach revealed C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5 genes to be important in chromosomal instability-related adenoma to carcinoma progression. These genes therefore may serve as highly specific biomarkers for colorectal cancer with potential clinical applications

Magnetic effects at the interface between nonmagnetic oxides

The electronic reconstruction at the interface between two insulating oxides can give rise to a highly-conductive interface. In analogy to this remarkable interface-induced conductivity we show how, additionally, magnetism can be induced at the interface between the otherwise nonmagnetic insulating perovskites SrTiO3 and LaAlO3. A large negative magnetoresistance of the interface is found, together with a logarithmic temperature dependence of the sheet resistance. At low temperatures, the sheet resistance reveals magnetic hysteresis. Magnetic ordering is a key issue in solid-state science and its underlying mechanisms are still the subject of intense research. In particular, the interplay between localized magnetic moments and the spin of itinerant conduction electrons in a solid gives rise to intriguing many-body effects such as Ruderman-Kittel-Kasuya-Yosida (RKKY) interactions, the Kondo effect, and carrier-induced ferromagnetism in diluted magnetic semiconductors. The conducting oxide interface now provides a versatile system to induce and manipulate magnetic moments in otherwise nonmagnetic materials.Comment: Nature Materials, July issu

Deletion of chromosome 4q predicts outcome in Stage II colon cancer patients

Background: Around 30% of all stage II colon cancer patients will relapse and die of their disease. At present no objective parameters to identify high-risk stage II colon cancer patients, who will benefit from adjuvant chemotherapy, have been established. With traditional histopathological features definition of high-risk stage II colon cancer patients is inaccurate. Therefore more objective and robust markers for prediction of relapse are needed. DNA copy number aberrations have proven to be robust prognostic markers, but have not yet been investigated for this specific group of patients. The aim of the present study was to identify chromosomal aberrations that can predict relapse of tumor in patients with stage II colon cancer

Reduced genomic tumor heterogeneity after neoadjuvat chemotherapy is related to favorable outcome in patients with esophageal adenocarcinoma

Neoadjuvant chemo(radio)therapy followed by surgery is the standard of care for patients with locally advanced resectable esophageal adenocarcinoma (EAC). There is increasing evidence that drug resistance might be related to genomic heterogeneity. We investigated whether genomic tumor heterogeneity is different after cytotoxic chemotherapy and is associated with EAC patient survival. We used arrayCGH and a quantitative assessment of the whole genome DNA copy number aberration patterns (‘DNA copy number entropy’) to establish the level of genomic tumor heterogeneity in 80 EAC treated with neoadjuvant chemotherapy followed by surgery (CS group) or surgery alone (S group). The association between DNA copy number entropy, clinicopathological variables and survival was investigated. DNA copy number entropy was reduced after chemotherapy, even if there was no morphological evidence of response to therapy (p<0.001). Low DNA copy number entropy was associated with improved survival in the CS group (p=0.011) but not in the S group (p=0.396). Our results suggest that cytotoxic chemotherapy reduces DNA copy number entropy, which might be a more sensitive tumor response marker than changes in the morphological tumor phenotype. The use of DNA copy number entropy in clinical practice will require validation of our results in a prospective study

Spin qubits with electrically gated polyoxometalate molecules

Spin qubits offer one of the most promising routes to the implementation of quantum computers. Very recent results in semiconductor quantum dots show that electrically-controlled gating schemes are particularly well-suited for the realization of a universal set of quantum logical gates. Scalability to a larger number of qubits, however, remains an issue for such semiconductor quantum dots. In contrast, a chemical bottom-up approach allows one to produce identical units in which localized spins represent the qubits. Molecular magnetism has produced a wide range of systems with tailored properties, but molecules permitting electrical gating have been lacking. Here we propose to use the polyoxometalate [PMo12O40(VO)2]q-, where two localized spins-1/2 can be coupled through the electrons of the central core. Via electrical manipulation of the molecular redox potential, the charge of the core can be changed. With this setup, two-qubit gates and qubit readout can be implemented.Comment: 9 pages, 6 figures, to appear in Nature Nanotechnolog

Gene Network Reconstruction using Global-Local Shrinkage Priors

Reconstructing a gene network from high-throughput molecular data is an important but challenging task, as the number of parameters to estimate easily is much larger than the sample size. A conventional remedy is to regularize or penalize the model likelihood. In network models, this is often done $\textit{locally}$ in the neighborhood of each node or gene. However, estimation of the many regularization parameters is often difficult and can result in large statistical uncertainties. In this paper we propose to combine local regularization with $\textit{global}$ shrinkage of the regularization parameters to borrow strength between genes and improve inference. We employ a simple Bayesian model with nonsparse, conjugate priors to facilitate the use of fast variational approximations to posteriors. We discuss empirical Bayes estimation of hyperparameters of the priors, and propose a novel approach to rank-based posterior thresholding. Using extensive model- and data-based simulations, we demonstrate that the proposed inference strategy outperforms popular (sparse) methods, yields more stable edges, and is more reproducible. The proposed method, termed $\texttt{ShrinkNet}$, is then applied to Glioblastoma to investigate the interactions between genes associated with patient survival.This work was supported by the Center for Medical Systems Biology (CMSB), and the European Union Grant EpiRadBio, established by the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NGI/NWO), nr. FP7-269553