Combining individual p-values to aggregate multiple small effects has a long-standing interest in statistics, dating back to the classic Fisher's combination test. In modern large-scale data analysis, correlation and sparsity are common features and efficient computation is a necessary requirement for dealing with massive data. To overcome these challenges, we propose a new test that takes advantage of the Cauchy distribution. Our test statistic has a very simple form and is defined as a weighted sum of Cauchy transformation of individual p-values. We prove a non-asymptotic result that the tail of the null distribution of our proposed test statistic can be well approximated by a Cauchy distribution under arbitrary dependency structures. Based on this theoretical result, the p-value calculation of our proposed test is not only accurate, but also as simple as the classic z-test or t-test, making our test well suited for analyzing massive data. We further show that the power of the proposed test is asymptotically optimal in a strong sparsity setting. Extensive simulations demonstrate that the proposed test has both strong power against sparse alternatives and a good accuracy with respect to p-value calculations, especially for very small p-values. The proposed test has also been applied to a genome-wide association study of Crohn's disease and compared with several existing tests.

Estimation and group comparison of survival curves are two very common issues in survival analysis. In practice, the Kaplan-Meier estimates of survival functions may be biased due to unbalanced distribution of confounders. Here we develop an adjusted Kaplan-Meier estimator (AKME) to reduce confounding effects using inverse probability of treatment weighting (IPTW). Each observation is weighted by its inverse probability of being in a certain group. The AKME is shown to be a consistent estimate of the survival function, and the variance of the AKME is derived. A weighted log-rank test is proposed for comparing group differences of survival functions. Simulation studies are used to illustrate the performance of AKME and the weighted log-rank test. The method proposed here outperforms the Kaplan-Meier estimate, and it does better than or as well as other estimators based on stratification. The AKME and the weighted log-rank test are applied to two real examples: one is the study of times to reinfection of sexually transmitted diseases, and the other is the primary biliary cirrhosis (PBC) study.

It was previously reported that three dsRNA segments, designated L, M and S, were isolated from Sclerotinia sclerotiorum strain Ep-1PN and that the M dsRNA segment was coincident with hypovirulence and debilitation of the fungal host. Here, the complete nucleotide sequence of the M dsRNA of 5419 nt, excluding the poly(A) tail, was determined. Sequence analysis revealed the occurrence of a single open reading frame (nt 93-5195) encoding a protein with significant similarity to the replicases of the 'alphavirus-like' supergroup of positive-strand RNA viruses. The M dsRNA-encoded putative replicase protein contained the conserved methyl transferase, helicase and RNA-dependent RNA polymerase (RdRp) domains characteristic of the replicases of potex-like plant viruses (flexiviruses) and Botrytis virus F (BVF), a flexuous rod mycovirus infecting the phytopathogenic fungus Botrytis cinerea. Furthermore, convincing evidence is presented showing that ascospore descendents derived from the debilitated strain Ep-1PN were devoid of dsRNA and exhibited normal colony morphology. Moreover, it was demonstrated that the debilitation phenotype was transmitted from the parental debilitated strain to its normal ascospore progeny via hyphal anastomosis. These results suggest that the M dsRNA from strain Ep-1PN is derived from the genomic RNA of a positive-strand RNA virus, which we designated Sclerotinia sclerotiorum debilitation-associated RNA virus (SsDRV). Although phylogenetic analysis of the conserved RdRp motifs verified that SsDRV is closely related to BVF and to the allexiviruses in the family Flexiviridae, SsDRV is distinct from these viruses, mainly based on the lack of coat protein and movement protein. INTRODUCTIONHypovirulent or debilitated strains of plant-pathogenic fungi that carry transmissible viruses have attracted much interest because of their potential exploitation as biological control agents, as well as their use as probes for deciphering mechanisms of fungal pathogenesis. Evidence of a viral aetiology for the debilitating disease of the plant-pathogenic fungus Cochliobolus (Helminthosporium) victoriae, the causal agent of Victoria blight of oats (Lindberg, 1959), was recently presented (Ghabrial, 2001;Ghabrial et al., 2002). Hypovirulent strains of Cryphonectria (Endothia) parasitica, the highly destructive chestnut blight fungus, were first reported in 1965 (Grente, 1965) and were later utilized successfully to control chestnut blight in Europe (Anagnostakis, 1982). The development of an infectious cDNA-based reverse genetics system for hypoviruses has significantly facilitated the undertaking of fundamental studies on various aspects of hypovirus-Cryphonectria parasitica interactions (Dawe & Nuss, 2001). There are several other examples of mycovirusassociated hypovirulence/debilitation including the mitoviruses in Ophiostoma novo-ulmi (Hong et al., 1999) and Sclerotinia homoeocarpa (Deng & Boland, 2004;Deng et al., 2003) and the unclassified mycoviruses infecting Diaporthe ambigua (Preisig et al., 2000), Fu...

Global analyses of protein complex assembly, composition, and location are needed to fully understand how cells coordinate diverse metabolic, mechanical, and developmental activities. The most common methods for proteome-wide analysis of protein complexes rely on affinity purification-mass spectrometry or yeast two-hybrid approaches. These methods are time consuming and are not suitable for many plant species that are refractory to transformation or genome-wide cloning of open reading frames. Here, we describe the proof of concept for a method allowing simultaneous global analysis of endogenous protein complexes that begins with intact leaves and combines chromatographic separation of extracts from subcellular fractions with quantitative label-free protein abundance profiling by liquid chromatography-coupled mass spectrometry. Applying this approach to the crude cytosolic fraction of Arabidopsis thaliana leaves using size exclusion chromatography, we identified hundreds of cytosolic proteins that appeared to exist as components of stable protein complexes. The reliability of the method was validated by protein immunoblot analysis and comparisons with published size exclusion chromatography data and the masses of known complexes. The method can be implemented with appropriate instrumentation, is applicable to any biological system, and has the potential to be further developed to characterize the composition of protein complexes and measure the dynamics of protein complex localization and assembly under different conditions.

Mammary intraepithelial lesions (IEL) are nowadays frequently diagnosed as a result of the success of mammographic screening, education programs, and awareness by women. Establishment of an animal model for these lesions to test treatment or preventive modalities is a prerequisite for human clinical trials. A model for spontaneous IELs, especially for estrogen receptor (ER)-negative lesions, does not exist. This study describes the histologic and immunohistochemical similarity between human and canine mammary IELs. Mammary tumors from 200 dogs were classified and histologic sections of the excisional specimens were evaluated for IELs. IELs, found in specimens from 60 dogs, were categorized as adenosis, sclerosing adenosis, intraductal papilloma, sclerosing papilloma, ductal hyperplasia, atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS; high, intermediate, and low grade). Most proliferative IELs without atypia were associated with benign tumors, whereas IELs with atypia (ADH and DCIS) were generally associated with mammary cancer. ER-A expression was significantly low or absent in most ADH and DCIS lesions as well as in their associated tumors. Ki67 expression was significantly higher in high-grade DCIS than in hyperplasia or low-grade DCIS. Two thirds of high-grade DCIS lesions were positive for HER-2. Canine mammary IELs were strikingly similar to those of the human breast. The frequency of IELs in the dog, their association with spontaneous mammary cancer, their pattern of ER-A and HER-2 expression, and their histologic resemblance to human IELs may make the dog an ideal model to study human ER-negative (both HER-2 positive and negative) breast cancer progression as well as prevention and treatment. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2247 -56)