Significant distinct branches of hierarchical trees: a framework for statistical analysis and applications to biological data

Abstract Background: One of the most common goals of hierarchical clustering is finding those branches of a tree that form quantifiably distinct data subtypes. Achieving this goal in a statistically meaningful way requires (a) a measure of distinctness of a branch and (b) a test to determine the significance of the observed measure, applicable to all branches and across multiple scales of dissimilarity

A realistic heat bath: theory and application to kink-antikink dynamics

We propose a new method of studying a real-time canonical evolution of field-theoretic systems with boundary coupling to a realistic heat bath. In the free-field case the method is equivalent to an infinite extension of the system beyond the boundary, while in the interacting case the extension of the system is done in linear approximation. We use this technique to study kink-antikink dynamics in $\varphi^4$ field theory in 1+1 dimensions.Comment: 21 pages including 7 figures (the shar file includes the tex file + 7 postscript files for figures). IUHET-241, IPS-92-29, UALG-PHYS-1

Accurate and robust inference of genetic ancestry from cancer-derived molecular data across genomic platforms

Genetic ancestry-oriented cancer research requires the ability to perform accurate and robust ancestry inference from existing cancer-derived data, including whole exomes, transcriptomes and targeted gene panels, very often in the absence of matching cancer-free genomic data. In order to optimize and assess the performance of the ancestry inference for any given input cancer-derived molecular profile, we develop a data synthesis framework. In its core procedure, the ancestral background of the profiled patient is replaced with one of any number of individuals with known ancestry. Data synthesis is applicable to multiple profiling platforms and makes it possible to assess the performance of inference separately for each continental-level ancestry. This ability extends to all ancestries, including those without statistically sufficient representation in the existing cancer data. We further show that our inference procedure is accurate and robust in a wide range of sequencing depths. Testing our approach for three representative cancer types, and across three molecular profiling modalities, we demonstrate that global, continental-level ancestry of the patient can be inferred with high accuracy, as quantified by its agreement with the golden standard of the ancestry derived from matching cancer-free molecular data. Our study demonstrates that vast amounts of existing cancer-derived molecular data potentially are amenable to ancestry-oriented studies of the disease, without recourse to matching cancer-free genomes or patients’ self-identification by ancestry

Genetic ancestry inference from cancer-derived molecular data across genomic and transcriptomic platforms

Genetic ancestry-oriented cancer research requires the ability to perform accurate and robust genetic ancestry inference from existing cancer-derived data, including whole exome sequencing, transcriptome sequencing, and targeted gene panels, very often in the absence of matching cancer-free genomic data. Here we examined the feasibility and accuracy of computational inference of genetic ancestry relying exclusively on cancer-derived data. A data synthesis framework was developed to optimize and assess the performance of the ancestry inference for any given input cancer-derived molecular profile. In its core procedure, the ancestral background of the profiled patient is replaced with one of any number of individuals with known ancestry. The data synthesis framework is applicable to multiple profiling platforms, making it possible to assess the performance of inference specifically for a given molecular profile and separately for each continental-level ancestry; this ability extends to all ancestries, including those without statistically sufficient representation in the existing cancer data. The inference procedure was demonstrated to be accurate and robust in a wide range of sequencing depths. Testing of the approach in four representative cancer types and across three molecular profiling modalities showed that continental-level ancestry of patients can be inferred with high accuracy, as quantified by its agreement with the gold standard of deriving ancestry from matching cancer-free molecular data. This study demonstrates that vast amounts of existing cancer-derived molecular data are potentially amenable to ancestry-oriented studies of the disease without requiring matching cancer-free genomes or patient self-reported ancestry

Multiplex Accurate Sensitive Quantitation (MASQ) With Application to Minimal Residual Disease in Acute Myeloid Leukemia

Measuring minimal residual disease in cancer has applications for prognosis, monitoring treatment and detection of recurrence. Simple sequence-based methods to detect nucleotide substitution variants have error rates (about 10-3) that limit sensitive detection. We developed and characterized the performance of MASQ (multiplex accurate sensitive quantitation), a method with an error rate below 10-6. MASQ counts variant templates accurately in the presence of millions of host genomes by using tags to identify each template and demanding consensus over multiple reads. Since the MASQ protocol multiplexes 50 target loci, we can both integrate signal from multiple variants and capture subclonal response to treatment. Compared to existing methods for variant detection, MASQ achieves an excellent combination of sensitivity, specificity and yield. We tested MASQ in a pilot study in acute myeloid leukemia (AML) patients who entered complete remission. We detect leukemic variants in the blood and bone marrow samples of all five patients, after induction therapy, at levels ranging from 10-2 to nearly 10-6. We observe evidence of sub-clonal structure and find higher target variant frequencies in patients who go on to relapse, demonstrating the potential for MASQ to quantify residual disease in AML

Copolymerization of single-cell nucleic acids into balls of acrylamide gel

We show the use of 5'-Acrydite oligonucleotides to copolymerize single-cell DNA or RNA into balls of acrylamide gel (BAGs). Combining this step with split-and-pool techniques for creating barcodes yields a method with advantages in cost and scalability, depth of coverage, ease of operation, minimal cross-contamination, and efficient use of samples. We perform DNA copy number profiling on mixtures of cell lines, nuclei from frozen prostate tumors, and biopsy washes. As applied to RNA, the method has high capture efficiency of transcripts and sufficient consistency to clearly distinguish the expression patterns of cell lines and individual nuclei from neurons dissected from the mouse brain. By using varietal tags (UMIs) to achieve sequence error correction, we show extremely low levels of cross-contamination by tracking source-specific SNVs. The method is readily modifiable, and we will discuss its adaptability and diverse applications

Microscopic Formulation of Black Holes in String Theory

In this Report we review the microscopic formulation of the five dimensional black hole of type IIB string theory in terms of the D1-D5 brane system. The emphasis here is more on the brane dynamics than on supergravity solutions. We show how the low energy brane dynamics, combined with crucial inputs from AdS/CFT correspondence, leads to a derivation of black hole thermodynamics and the rate of Hawking radiation. Our approach requires a detailed exposition of the gauge theory and conformal field theory of the D1-D5 system. We also discuss some applications of the AdS/CFT correspondence in the context of black hole formation in three dimensions by thermal transition and by collision of point particles.Comment: (v2) To appear in Physics Reports; 168 pages, 4 figures. References and clarifications adde

Centrality and sNNDependenceofthe\sqrt{s_{NN}} Dependence of the dE_{T}/d\etaand and dN_{ch}/d\eta$ in Heavy Ion Collisions at Mid-Rapidity

The PHENIX experiment at RHIC has measured transverse energy and charged particle multiplicity at mid-rapidity in Au + Au collisions at $\sqrt{s_{NN}}$ = 19.6, 130, 62.4 and 200 GeV as a function of centrality. The presented results are compared to measurements from other RHIC experiments, and experiments at lower energies. The $\sqrt{s_{NN}}$ dependence of $dE_{T}/d\eta$ and $dN_{ch}/d\eta$ per pair of participants is consistent with logarithmic scaling for the most central events. The centrality dependence of $dE_{T}/d\eta$ and $dN_{ch}/d\eta$ is similar at all measured incident energies. At RHIC energies the ratio of transverse energy per charged particle was found independent of centrality and growing slowly with $\sqrt{s_{NN}}$. A survey of comparisons between the data and available theoretical models is also presented.Comment: Proccedings of the Workshop: Focus on Multiplcity at Bari, Italy, June 17-19,2004. To be submitted to the Jornal of Physics, "Conference series". Includes: 20 Pages, 15 figures, 3 Tables, 80 Referencie

Functional Identification of Tumor Suppressor Genes Through an in vivo RNA Interference Screen in a Mouse Lymphoma Model

2010 April 6Short hairpin RNAs (shRNAs) capable of stably suppressing gene function by RNA interference (RNAi) can mimic tumor-suppressor-gene loss in mice. By selecting for shRNAs capable of accelerating lymphomagenesis in a well-characterized mouse lymphoma model, we identified over ten candidate tumor suppressors, including Sfrp1, Numb, Mek1, and Angiopoietin 2. Several components of the DNA damage response machinery were also identified, including Rad17, which acts as a haploinsufficient tumor suppressor that responds to oncogenic stress and whose loss is associated with poor prognosis in human patients. Our results emphasize the utility of in vivo RNAi screens, identify and validate a diverse set of tumor suppressors, and have therapeutic implications

Centrality Dependence of the High p_T Charged Hadron Suppression in Au+Au collisions at sqrt(s_NN) = 130 GeV

PHENIX has measured the centrality dependence of charged hadron p_T spectra from central Au+Au collisions at sqrt(s_NN)=130 GeV. The truncated mean p_T decreases with centrality for p_T > 2 GeV/c, indicating an apparent reduction of the contribution from hard scattering to high p_T hadron production. For central collisions the yield at high p_T is shown to be suppressed compared to binary nucleon-nucleon collision scaling of p+p data. This suppression is monotonically increasing with centrality, but most of the change occurs below 30% centrality, i.e. for collisions with less than about 140 participating nucleons. The observed p_T and centrality dependence is consistent with the particle production predicted by models including hard scattering and subsequent energy loss of the scattered partons in the dense matter created in the collisions.Comment: 7 pages text, LaTeX, 6 figures, 2 tables, 307 authors, resubmitted to Phys. Lett. B. Revised to address referee concerns. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are publicly available at http://www.phenix.bnl.gov/phenix/WWW/run/phenix/papers.htm