Showing papers by "Stanford University published in 2010"

Regularization Paths for Generalized Linear Models via Coordinate Descent

Abstract: We develop fast algorithms for estimation of generalized linear models with convex penalties. The models include linear regression, two-class logistic regression, and multinomial regression problems while the penalties include l(1) (the lasso), l(2) (ridge regression) and mixtures of the two (the elastic net). The algorithms use cyclical coordinate descent, computed along a regularization path. The methods can handle large problems and can also deal efficiently with sparse features. In comparative timings we find that the new algorithms are considerably faster than competing methods.

The next generation of scenarios for climate change research and assessment

Abstract: Advances in the science and observation of climate change are providing a clearer understanding of the inherent variability of Earth's climate system and its likely response to human and natural influences. The implications of climate change for the environment and society will depend not only on the response of the Earth system to changes in radiative forcings, but also on how humankind responds through changes in technology, economies, lifestyle and policy. Extensive uncertainties exist in future forcings of and responses to climate change, necessitating the use of scenarios of the future to explore the potential consequences of different response options. To date, such scenarios have not adequately examined crucial possibilities, such as climate change mitigation and adaptation, and have relied on research processes that slowed the exchange of information among physical, biological and social scientists. Here we describe a new process for creating plausible scenarios to investigate some of the most challenging and important questions about climate change confronting the global community.

A Singular Value Thresholding Algorithm for Matrix Completion

Abstract: This paper introduces a novel algorithm to approximate the matrix with minimum nuclear norm among all matrices obeying a set of convex constraints. This problem may be understood as the convex relaxation of a rank minimization problem and arises in many important applications as in the task of recovering a large matrix from a small subset of its entries (the famous Netflix problem). Off-the-shelf algorithms such as interior point methods are not directly amenable to large problems of this kind with over a million unknown entries. This paper develops a simple first-order and easy-to-implement algorithm that is extremely efficient at addressing problems in which the optimal solution has low rank. The algorithm is iterative, produces a sequence of matrices $\{\boldsymbol{X}^k,\boldsymbol{Y}^k\}$, and at each step mainly performs a soft-thresholding operation on the singular values of the matrix $\boldsymbol{Y}^k$. There are two remarkable features making this attractive for low-rank matrix completion problems. The first is that the soft-thresholding operation is applied to a sparse matrix; the second is that the rank of the iterates $\{\boldsymbol{X}^k\}$ is empirically nondecreasing. Both these facts allow the algorithm to make use of very minimal storage space and keep the computational cost of each iteration low. On the theoretical side, we provide a convergence analysis showing that the sequence of iterates converges. On the practical side, we provide numerical examples in which $1,000\times1,000$ matrices are recovered in less than a minute on a modest desktop computer. We also demonstrate that our approach is amenable to very large scale problems by recovering matrices of rank about 10 with nearly a billion unknowns from just about 0.4% of their sampled entries. Our methods are connected with the recent literature on linearized Bregman iterations for $\ell_1$ minimization, and we develop a framework in which one can understand these algorithms in terms of well-known Lagrange multiplier algorithms.

Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis

Abstract: Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.

Saliency, switching, attention and control: a network model of insula function

Abstract: The insula is a brain structure implicated in disparate cognitive, affective, and regulatory functions, including interoceptive awareness, emotional responses, and empathic processes. While classically considered a limbic region, recent evidence from network analysis suggests a critical role for the insula, particularly the anterior division, in high-level cognitive control and attentional processes. The crucial insight and view we present here is of the anterior insula as an integral hub in mediating dynamic interactions between other large-scale brain networks involved in externally oriented attention and internally oriented or self-related cognition. The model we present postulates that the insula is sensitive to salient events, and that its core function is to mark such events for additional processing and initiate appropriate control signals. The anterior insula and the anterior cingulate cortex form a “salience network” that functions to segregate the most relevant among internal and extrapersonal stimuli in order to guide behavior. Within the framework of our network model, the disparate functions ascribed to the insula can be conceptualized by a few basic mechanisms: (1) bottom–up detection of salient events, (2) switching between other large-scale networks to facilitate access to attention and working memory resources when a salient event is detected, (3) interaction of the anterior and posterior insula to modulate autonomic reactivity to salient stimuli, and (4) strong functional coupling with the anterior cingulate cortex that facilitates rapid access to the motor system. In this manner, with the insula as its integral hub, the salience network assists target brain regions in the generation of appropriate behavioral responses to salient stimuli. We suggest that this framework provides a parsimonious account of insula function in neurotypical adults, and may provide novel insights into the neural basis of disorders of affective and social cognition.

GREAT improves functional interpretation of cis-regulatory regions

Abstract: We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome. Whereas previous methods took into account only binding proximal to genes, GREAT is able to properly incorporate distal binding sites and control for false positives using a binomial test over the input genomic regions. GREAT incorporates annotations from 20 ontologies and is available as a web application. Applying GREAT to data sets from chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) of multiple transcription-associated factors, including SRF, NRSF, GABP, Stat3 and p300 in different developmental contexts, we recover many functions of these factors that are missed by existing gene-based tools, and we generate testable hypotheses. The utility of GREAT is not limited to ChIP-seq, as it could also be applied to open chromatin, localized epigenomic markers and similar functional data sets, as well as comparative genomics sets.

Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns

Abstract: Upon delivery, the neonate is exposed for the first time to a wide array of microbes from a variety of sources, including maternal bacteria. Although prior studies have suggested that delivery mode shapes the microbiota's establishment and, subsequently, its role in child health, most researchers have focused on specific bacterial taxa or on a single body habitat, the gut. Thus, the initiation stage of human microbiome development remains obscure. The goal of the present study was to obtain a community-wide perspective on the influence of delivery mode and body habitat on the neonate's first microbiota. We used multiplexed 16S rRNA gene pyrosequencing to characterize bacterial communities from mothers and their newborn babies, four born vaginally and six born via Cesarean section. Mothers' skin, oral mucosa, and vagina were sampled 1 h before delivery, and neonates' skin, oral mucosa, and nasopharyngeal aspirate were sampled <5 min, and meconium <24 h, after delivery. We found that in direct contrast to the highly differentiated communities of their mothers, neonates harbored bacterial communities that were undifferentiated across multiple body habitats, regardless of delivery mode. Our results also show that vaginally delivered infants acquired bacterial communities resembling their own mother's vaginal microbiota, dominated by Lactobacillus, Prevotella, or Sneathia spp., and C-section infants harbored bacterial communities similar to those found on the skin surface, dominated by Staphylococcus, Corynebacterium, and Propionibacterium spp. These findings establish an important baseline for studies tracking the human microbiome's successional development in different body habitats following different delivery modes, and their associated effects on infant health.

Biological, clinical and population relevance of 95 loci for blood lipids

Abstract: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes

Abstract: Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.

CoSaMP: iterative signal recovery from incomplete and inaccurate samples

Abstract: Compressive sampling (CoSa) is a new paradigm for developing data sampling technologies It is based on the principle that many types of vector-space data are compressible, which is a term of art in mathematical signal processing The key ideas are that randomized dimension reduction preserves the information in a compressible signal and that it is possible to develop hardware devices that implement this dimension reduction efficiently The main computational challenge in CoSa is to reconstruct a compressible signal from the reduced representation acquired by the sampling device This extended abstract describes a recent algorithm, called, CoSaMP, that accomplishes the data recovery task It was the first known method to offer near-optimal guarantees on resource usage

Review of Particle Physics

Abstract: This biennial Review summarizes much of particle physics. Using data from previous editions, plus 2158 new measurements from 551 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We also summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors, probability, and statistics. Among the 108 reviews are many that are new or heavily revised including those on neutrino mass, mixing, and oscillations, QCD, top quark, CKM quark-mixing matrix, V-ud & V-us, V-cb & V-ub, fragmentation functions, particle detectors for accelerator and non-accelerator physics, magnetic monopoles, cosmological parameters, and big bang cosmology.

Significant Acidification in Major Chinese Croplands

Abstract: Soil acidification is a major problem in soils of intensive Chinese agricultural systems. We used two nationwide surveys, paired comparisons in numerous individual sites, and several long-term monitoring-field data sets to evaluate changes in soil acidity. Soil pH declined significantly ( P + ) per hectare per year, and base cations uptake contributed a further 15 to 20 kilomoles of H + per hectare per year to soil acidification in four widespread cropping systems. In comparison, acid deposition (0.4 to 2.0 kilomoles of H + per hectare per year) made a small contribution to the acidification of agricultural soils across China.

Direct conversion of fibroblasts to functional neurons by defined factors

Abstract: Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modelling and regenerative medicine.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Abstract: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Highly sensitive flexible pressure sensors with microstructured rubber dielectric layers

Abstract: The development of an electronic skin is critical to the realization of artificial intelligence that comes into direct contact with humans, and to biomedical applications such as prosthetic skin. To mimic the tactile sensing properties of natural skin, large arrays of pixel pressure sensors on a flexible and stretchable substrate are required. We demonstrate flexible, capacitive pressure sensors with unprecedented sensitivity and very short response times that can be inexpensively fabricated over large areas by microstructuring of thin films of the biocompatible elastomer polydimethylsiloxane. The pressure sensitivity of the microstructured films far surpassed that exhibited by unstructured elastomeric films of similar thickness, and is tunable by using different microstructures. The microstructured films were integrated into organic field-effect transistors as the dielectric layer, forming a new type of active sensor device with similarly excellent sensitivity and response times.

Nomenclature for factors of the HLA system, 2010.

Abstract: The WHO Nomenclature Committee for Factors of the HLA System met following the 14th International HLA and Immunogenetics Workshop in Melbourne, Australia in December 2005 and Buzios, Brazil during the 15th International HLA and Immunogenetics Workshop in September 2008. This report documents the additions and revisions to the nomenclature of HLA specificities following the principles established in previous reports (1–18).

Variance component model to account for sample structure in genome-wide association studies

Abstract: Although genome-wide association studies (GWASs) have identified numerous loci associated with complex traits, imprecise modeling of the genetic relatedness within study samples may cause substantial inflation of test statistics and possibly spurious associations. Variance component approaches, such as efficient mixed-model association (EMMA), can correct for a wide range of sample structures by explicitly accounting for pairwise relatedness between individuals, using high-density markers to model the phenotype distribution; but such approaches are computationally impractical. We report here a variance component approach implemented in publicly available software, EMMA eXpedited (EMMAX), that reduces the computational time for analyzing large GWAS data sets from years to hours. We apply this method to two human GWAS data sets, performing association analysis for ten quantitative traits from the Northern Finland Birth Cohort and seven common diseases from the Wellcome Trust Case Control Consortium. We find that EMMAX outperforms both principal component analysis and genomic control in correcting for sample structure.

Neonatal Outcomes of Extremely Preterm Infants From the NICHD Neonatal Research Network

Abstract: OBJECTIVE: This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA). METHODS: Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22–28 weeks) and very low birth weight (401–1500 g) who were born at network centers between January 1, 2003, and December 31, 2007. RESULTS: Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at ≤12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respiratory distress syndrome, 46% patent ductus arteriosus, 16% severe intraventricular hemorrhage, 11% necrotizing enterocolitis, and 36% late-onset sepsis. The new severity-based definition of bronchopulmonary dysplasia classified more infants as having bronchopulmonary dysplasia than did the traditional definition of supplemental oxygen use at 36 weeks (68%, compared with 42%). More than one-half of infants with extremely low GAs had undetermined retinopathy status at the time of discharge. Center differences in management and outcomes were identified. CONCLUSION: Although the majority of infants with GAs of ≥24 weeks survive, high rates of morbidity among survivors continue to be observed.

The genetic landscape of a cell.

Abstract: A genome-scale genetic interaction map was constructed by examining 5.4 million gene-gene pairs for synthetic genetic interactions, generating quantitative genetic interaction profiles for ~75% of all genes in the budding yeast, Saccharomyces cerevisiae. A network based on genetic interaction profiles reveals a functional map of the cell in which genes of similar biological processes cluster together in coherent subsets, and highly correlated profiles delineate specific pathways to define gene function. The global network identifies functional cross-connections between all bioprocesses, mapping a cellular wiring diagram of pleiotropy. Genetic interaction degree correlated with a number of different gene attributes, which may be informative about genetic network hubs in other organisms. We also demonstrate that extensive and unbiased mapping of the genetic landscape provides a key for interpretation of chemical-genetic interactions and drug target identification.

The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis

Abstract: Criteria for the classification of giant cell (temporal) arteritis were developed by comparing 214 patients who had this disease with 593 patients with other forms of vasculitis. For the traditional format classification, 5 criteria were selected: age greater than or equal to 50 years at disease onset, new onset of localized headache, temporal artery tenderness or decreased temporal artery pulse, elevated erythrocyte sedimentation rate (Westergren) greater than or equal to 50 mm/hour, and biopsy sample including an artery, showing necrotizing arteritis, characterized by a predominance of mononuclear cell infiltrates or a granulomatous process with multinucleated giant cells. The presence of 3 or more of these 5 criteria was associated with a sensitivity of 93.5% and a specificity of 91.2%. A classification tree was also constructed using 6 criteria. These criteria were the same as for the traditional format, except that elevated erythrocyte sedimentation rate was excluded, and 2 other variables were included: scalp tenderness and claudication of the jaw or tongue or on deglutition. The classification tree was associated with a sensitivity of 95.3% and specificity of 90.7%.

Narrow graphene nanoribbons from carbon nanotubes

Abstract: Disclosed is a method for making graphene nanoribbons (GNRs) by controlled unzipping of structures such as carbon nanotubes (CNTs) by etching (e.g., argon plasma etching) of nanotubes partly embedded in a polymer film. The GNRs have smooth edges and a narrow width distribution (2-20 nm). Raman spectroscopy and electrical transport measurements reveal the high quality of the GNRs. Such a method of unzipping CNTs with well-defined structures in an array will allow the production of GNRs with controlled widths, edge structures, placement and alignment in a scalable fashion for device integration. GNRs may be formed from nanostructures in a controlled array to form arrays of parallel or overlapping structures. Also disclosed is a method in which the CNTs are in a predetermined pattern that is carried over and transferred to a substrate for forming into a semiconductor device.

Epigenetic memory in induced pluripotent stem cells

Abstract: Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an 'epigenetic memory' of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment.

The American College of Rheumatology 1990 criteria for the classification of churg‐strauss syndrome (allergic granulomatosis and angiitis)

Abstract: Criteria for the classification of Churg-Strauss syndrome (CSS) were developed by comparing 20 patients who had this diagnosis with 787 control patients with other forms of vasculitis. For the traditional format classification, 6 criteria were selected: asthma, eosinophilia greater than 10% on differential white blood cell count, mononeuropathy (including multiplex) or polyneuropathy, non-fixed pulmonary infiltrates on roentgenography, paranasal sinus abnormality, and biopsy containing a blood vessel with extravascular eosinophils. The presence of 4 or more of these 6 criteria yielded a sensitivity of 85% and a specificity of 99.7%. A classification tree was also constructed with 3 selected criteria: asthma, eosinophilia greater than 10% on differential white blood cell count, and history of documented allergy other than asthma or drug sensitivity. If a subject has eosinophilia and a documented history of either asthma or allergy, then that subject is classified as having CSS. For the tree classification, the sensitivity was 95% and the specificity was 99.2%. Advantages of the traditional format compared with the classification tree format, when applied to patients with systemic vasculitis, and their comparison with earlier work on CSS are discussed.

Scalable Coating and Properties of Transparent, Flexible, Silver Nanowire Electrodes

Abstract: We report a comprehensive study of transparent and conductive silver nanowire (Ag NW) electrodes, including a scalable fabrication process, morphologies, and optical, mechanical adhesion, and flexibility properties, and various routes to improve the performance. We utilized a synthesis specifically designed for long and thin wires for improved performance in terms of sheet resistance and optical transmittance. Twenty Ω/sq and ∼80% specular transmittance, and 8 ohms/sq and 80% diffusive transmittance in the visible range are achieved, which fall in the same range as the best indium tin oxide (ITO) samples on plastic substrates for flexible electronics and solar cells. The Ag NW electrodes show optical transparencies superior to ITO for near-infrared wavelengths (2-fold higher transmission). Owing to light scattering effects, the Ag NW network has the largest difference between diffusive transmittance and specular transmittance when compared with ITO and carbon nanotube electrodes, a property which could gr...

Terrestrial phosphorus limitation: mechanisms, implications, and nitrogen–phosphorus interactions

Abstract: Nutrient limitation to primary productivity and other biological processes is widespread in terrestrial ecosystems, and nitrogen (N) and phosphorus (P) are the most common limiting elements, both individually and in combination. Mechanisms that drive P limitation, and their interactions with the N cycle, have received less attention than mechanisms causing N limitation. We identify and discuss six mechanisms that could drive P limitation in terrestrial ecosystems. The best known of these is depletion-driven limitation, in which accumulated P losses during long-term soil and ecosystem development contribute to what Walker and Syers termed a "terminal steady state" of profound P depletion and limitation. The other mechanisms are soil barriers that prevent access to P; transactional limitation, in which weathering of P-containing minerals does not keep pace with the supply of other resources; low-P parent materials; P sinks; and anthropogenic changes that increase the supply of other resources (often N) relative to P. We distinguish proximate nutrient limitation (which occurs where additions of a nutrient stimulate biological processes, especially productivity) from ultimate nutrient limitation (where additions of a nutrient can transform ecosystems). Of the mechanisms that drive P limitation, we suggest that depletion, soil barriers, and low-P parent material often cause ultimate limitation because they control the ecosystem mass balance of P. Similarly, demand-independent losses and constraints to N fixation can control the ecosystem-level mass balance of N and cause it to be an ultimate limiting nutrient.