Sergey V. Malov

The Novelty of Human Cancer/Testis Antigen Encoding Genes in Evolution

In order to be inherited in progeny generations, novel genes should originate in germ cells. Here, we suggest that the testes may play a special “catalyst” role in the birth and evolution of new genes. Cancer/testis antigen encoding genes (CT genes) are predominantly expressed both in testes and in a variety of tumors. By the criteria of evolutionary novelty, the CT genes are, indeed, novel genes. We performed homology searches for sequences similar to human CT in various animals and established that most of the CT genes are either found in humans only or are relatively recent in their origin. A majority of all human CT genes originated during or after the origin of Eutheria. These results suggest relatively recent origin of human CT genes and align with the hypothesis of the special role of the testes in the evolution of the gene families.

Semiparametric Regression Estimation in Copula Models

We consider some methods of semiparametric regression estimation in multivariate models when the common distribution function is represented using a copula and the marginals satisfy a generalized regression model using a transfer functional. Sufficient conditions for consistency and joint asymptotic normality of the finite-dimensional parameters are obtained.

GWATCH: a web platform for automated gene association discovery analysis

BackgroundAs genome-wide sequence analyses for complex human disease determinants are expanding, it is increasingly necessary to develop strategies to promote discovery and validation of potential disease-gene associations.FindingsHere we present a dynamic web-based platform – GWATCH – that automates and facilitates four steps in genetic epidemiological discovery: 1) Rapid gene association search and discovery analysis of large genome-wide datasets; 2) Expanded visual display of gene associations for genome-wide variants (SNPs, indels, CNVs), including Manhattan plots, 2D and 3D snapshots of any gene region, and a dynamic genome browser illustrating gene association chromosomal regions; 3) Real-time validation/replication of candidate or putative genes suggested from other sources, limiting Bonferroni genome-wide association study (GWAS) penalties; 4) Open data release and sharing by eliminating privacy constraints (The National Human Genome Research Institute (NHGRI) Institutional Review Board (IRB), informed consent, The Health Insurance Portability and Accountability Act (HIPAA) of 1996 etc.) on unabridged results, which allows for open access comparative and meta-analysis.ConclusionsGWATCH is suitable for both GWAS and whole genome sequence association datasets. We illustrate the utility of GWATCH with three large genome-wide association studies for HIV-AIDS resistance genes screened in large multicenter cohorts; however, association datasets from any study can be uploaded and analyzed by GWATCH.

Homogeneity Tests for Related Samples Under Censoring

We propose nonparametric homogeneity tests for related samples against much wider than location (or scale) class of alternatives including possible crossings of marginal cumulative distribution functions. The tests can be used in the case of complete and censored samples. Asymptotic distribution of the test statistics is investigated.

Semiparametric Estimation in Copulas with the Same Marginals

We consider semiparametric multivariate data models based on copula representation of the common distribution function. A copula is characterized by a parameter of association and marginal distribution functions. This parameter and the marginal distributions are unknown. In this article, we study the estimator of the parameter of association in copulas with the marginal distribution functions assumed as nuisance parameters restricted by the assumption that the components are identically distributed. Results of this work could be used to construct special kinds of tests of homogeneity for random vectors having dependent components.

Random variables generated by ranks in dependent schemes

Abstract. Some nonstationary sequences having independent vector of ranks and vector of order statistics are under consideration. We extend some characterizations in a class of independent r.v.s to a class of Archimedean copula processes and construct the interpretation which gives us a simple way for simulating Archimedean copula processes.

Life Table Estimator Revisited

ABSTRACT We explore the standard life table (actuarial) estimator for grouped right-censored survival data and its extensions in order to consider its relationship with the Kaplan–Meier estimator, and to investigate the critical properties of the extended life table estimators (ELTEs). We discuss certain conditions for the ELTE to be consistent and develop a characterization of the standard life table estimator using the consistency property under any choice of at least two observation times of a finite interval. We also perform a comparative analysis of the ELTEs with the corresponding maximum likelihood estimators for grouped right-censored survival data.

The Role of the Carcinoembryonic Antigen Receptor in Colorectal Cancer Progression

Clinical and experimental data suggest that carcinoembryonic antigen (CEA, CD66e, CEACAM-5) plays a key role in the formation of hepatic metastasis from colorectal and other types of epithelial cancers. The molecular events involved in CEA-induced metastasis have yet to be defined. Our group first cloned the gene (CEAR) for CEA-binding protein from the surface of fixed liver macrophages, (Kupffer cells). In this study to further elucidate the role of CEAR in colorectal cancer progression, its expression in colorectal cancer cells was suppressed by short hairpin RNAs (shRNAs) in CEA-overexpressing and CEA - negative MIP-101 colorectal cancer cell lines. The data show that targeted suppression of endogenous CEAR in tumor cells resulted in changes in cell invasiveness. RT-PCR data indicated reduced levels of E-cadherin, Snail, MMP-2, and Oct-4 in the clones with suppressed CEAR suggesting a role in the epithelial mesenchymal transition. The comparative analysis of tumorigenic activity to the liver of the cell lines with suppressed CEAR has also been conducted using an intrasplenic injection model in immuno-deficient mice. This data shows a decrease in tumor progression associated with CEAR suppression. In summary the results of this study revealed a novel role for CEAR gene in the regulation of colorectal cancer cell invasiveness and progression.

Signal Localization: A New Approach in Signal Discovery

A new approach for statistical association signal identification is developed in this paper. We consider a strategy for nonprecise signal identification by extending the well-known signal detection and signal identification methods applicable to the multiple testing problem. Collection of statistical instruments under the presented approach is much broader than under the traditional signal identification methods, allowing more efficient signal discovery. Further assessments of maximal value and average statistics in signal discovery are improved. While our method does not attempt to detect individual predictors, it instead detects sets of predictors that are jointly associated with the outcome. Therefore, an important application would be in genome wide association study (GWAS), where it can be used to detect genes which influence the phenotype but do not contain any individually significant single nucleotide polymorphism (SNP). We compare power of the signal identification method based on extremes of single p-values with the signal localization method based on average statistics for logarithms of p-values. A simulation analysis informs the application of signal localization using the average statistics for wide signals discovery in Gaussian white noise process. We apply average statistics and the localization method to GWAS to discover better gene influences of regulating loci in a Chinese cohort developed for risk of nasopharyngeal carcinoma (NPC).

141 Gene Discovery and Data Sharing in Genome Wide Association Analyses: lessons form AIDS genetic restriction genes

As genome wide association studies plus whole genome sequence analyses for complex human disease determinants are expanding, it seems useful to develop strategies to facilitate large data sharing, rapid replication and validation of provocative statistical associations that straddle the threshold for genome wide significance. At this conference, we shall announce GWATCH, (Genome Wide Association Tracks Chromosome Highway) a web based data release platform that can freely display and inspect unabridged genome tracked association data without compromising privacy or Informed Consent constrictions, allowing for rapid discovery and replication opportunities. We illustrate the utility with HIV-AIDS resistance genes screened in combined large multicenter cohort studies GWAS (MACS, HGDS, MHGS, ALLIVE, LSOCA HOMER) developed and studied over the last decades.