Biomedical subjects

Michael A Newton

Publications and source records attributed to Michael A Newton.

9 recordsLinked to original sources

PubMed2025

SURROGATE SELECTION OVERSAMPLES EXPANDED T CELL CLONOTYPES.

Surrogate selection is an experimental design that without sequencing any DNA can restrict a sample of cells to those carrying certain genomic mutations. In immunological disease studies, this design may provide a relatively easy approach to enrich a lymphocyte sample with cells relevant to the disease response because the emergence of neutral mutations associates with the proliferation history of clonal subpopulations. A statistical analysis of clonotype sizes provides a structured, quantitative perspective on this useful property of surrogate selection. Our model specification couples within-clonotype birth-death processes with an exchangeable model across clonotypes. Beyond enrichment questions about the surrogate selection design, our framework enables a study of sampling properties of elementary sample diversity statistics; it also points to new statistics that may usefully measure the burden of somatic genomic alterations associated with clonal expansion. We examine statistical properties of immunological samples governed by the coupled model specification, and we illustrate calculations in surrogate selection studies of melanoma and in single-cell genomic studies of T cell repertoires.

Bayes’s rule↗

PubMed2006

Genome-wide expression profiling reveals EBV-associated inhibition of MHC class I expression in nasopharyngeal carcinoma.

To identify the molecular mechanisms by which EBV-associated epithelial cancers are maintained, we measured the expression of essentially all human genes and all latent EBV genes in a collection of 31 laser-captured, microdissected nasopharyngeal carcinoma (NPC) tissue samples and 10 normal nasopharyngeal tissues. Global gene expression profiles clearly distinguished tumors from normal healthy epithelium. Expression levels of six viral genes (EBNA1, EBNA2, EBNA3A, EBNA3B, LMP1, and LMP2A) were correlated among themselves and strongly inversely correlated with the expression of a large subset of host genes. Among the human genes whose inhibition was most strongly correlated with increased EBV gene expression were multiple MHC class I HLA genes involved in regulating immune response via antigen presentation. The association between EBV gene expression and inhibition of MHC class I HLA expression implies that antigen display is either directly inhibited by EBV, facilitating immune evasion by tumor cells, and/or that tumor cells with inhibited presentation are selected for their ability to sustain higher levels of EBV to take maximum advantage of EBV oncogene-mediated tumor-promoting actions. Our data clearly reflect such tumor promotion, showing that deregulation of key proteins involved in apoptosis (BCL2-related protein A1 and Fas apoptotic inhibitory molecule), cell cycle checkpoints (AKIP, SCYL1, and NIN), and metastasis (matrix metalloproteinase 1) is closely correlated with the levels of EBV gene expression in NPC.

Biopsy↗

PubMed2006

On estimating the polyclonal fraction in lineage-marker studies of tumor origin.

Insight into the biology of tumor formation is provided by studies which demonstrate through the use of cell-lineage markers that some tumors have a polyclonal origin. Novelli et al. (1996) proposed to use the proportion of heterotypic tumors among the tumors that are either heterotypic or pure and of the minority marker type as a lower bound on the marginal fraction of polyclonal tumors. Generally, Novelli's ratio does not provide a valid lower bound for the marginal polyclonal fraction, as we demonstrate by analyzing relevant conditional probabilities. Estimation of the polyclonal fraction requires modeling assumptions on the distribution of the number of involved clones. Using three elementary models, we develop maximum likelihood estimation of the polyclonal fraction. We establish robustness of our estimates to misspecification of the clone-marking process, though the estimates are sensitive to assumptions about polyclonal mechanisms. On data from several published studies, our estimates of the polyclonal fraction are substantially smaller than Novelli's ratio.

Biometry↗

PubMed2006

A statistical test of the hypothesis that polyclonal intestinal tumors arise by random collision of initiated clones.

The random collision hypothesis is a mathematical idealization of intestinal tumor formation that can account for the polyclonal origin of tumors without requiring a mechanistic description of clonal interaction. Using data from recent polyclonality studies in mice, we develop a statistical procedure to test the random collision hypothesis. Elements from stochastic geometry and approximations due to Armitage (1949, Biometrika 36, 257-266) support a statistical model of tumor count data. Bayesian analysis yields the posterior distribution of the number of heterotypic tumors, from which p-values are computed to test random collision.

Animals↗

PubMed2006

Genes involved in DNA repair and nitrosamine metabolism and those located on chromosome 14q32 are dysregulated in nasopharyngeal carcinoma.

Polymorphisms in nitrosamine metabolism, DNA repair, and immune response genes have been associated with nasopharyngeal carcinoma (NPC). Studies have suggested chromosomal regions involved in NPC. To shed light on NPC etiology, we evaluated host gene expression patterns in 31 NPC and 10 normal nasopharyngeal tissue specimens using the Affymetrix Human Genome U133 Plus 2.0 Array. We focused on genes in five a priori biological pathways and chromosomal locations. Rates of differential expression within these prespecified lists and overall were tested using a bootstrap method. Differential expression was observed for 7.6% of probe sets overall. Elevations in rate of differential expression were observed within the DNA repair (13.7%; P = 0.01) and nitrosamine metabolism (17.5%; P = 0.04) pathways. Differentially expressed probe sets within the DNA repair pathway were consistently overexpressed (93%), with strong effects observed for PRKDC, PCNA, and CHEK1. Differentially expressed probe sets within the nitrosamine metabolism pathway were consistently underexpressed (100%), with strong effects observed for NQ01, CYP2B6, and CYP2E1. No significant evidence of increases in rate of differential expression was seen within the immune/inflammatory pathway. A significant elevation in rate of differential expression was noted for chromosome 4p15.1-4q12 (13.0%; P = 0.04); both overexpression and underexpression were evident (38% and 62%, respectively). An elevation in the rate of differential expression on chromosome 14q32 was observed (11.3%; P = 0.06) with a consistent pattern of gene underexpression (100%; P < 0.0001). These effects were similar when excluding late-stage tumors. Our results suggest that nitrosamine activation and DNA repair are important in NPC. The consistent down-regulation of expression on chromosome 14q32 suggests loss of heterozygosity in this region.

Biopsy↗

PubMed2005

Polyclonality of familial murine adenomas: analyses of mouse chimeras with low tumor multiplicity suggest short-range interactions.

In previous studies demonstrating the polyclonal structure of familial intestinal adenomas, high tumor multiplicity made it difficult to eliminate the possibility that polyclonality arose by the random collision of distinct initiated clones as opposed to some form of clonal interaction. We sought to test further the random collision hypothesis. Chimeric mice carrying the multiple intestinal neoplasia (Min) mutation of the adenomatous polyposis coli gene (Apc) and homozygous for the tumor resistance allele of the Mom1 locus were established. These chimeras also display a strong propensity for tumors of polyclonal structure, despite their markedly reduced tumor multiplicity. Considering tumor sizes and multiplicities, the observed fraction of overtly polyclonal heterotypic adenomas was significantly higher than predicted by the random collision hypothesis. This finding supports models of polyclonality involving interaction among multiple initiated clones. The extent of clonal interaction was assessed by statistical analyses that relate the observed frequency of overtly polyclonal heterotypic tumors to the geometry of the chimeric patches and the pattern of underlying crypts. These statistical calculations indicate that the familial adenomas of the Apc(Min/+) mouse may commonly form through interactions between clones as close as 1-2 crypt diameters apart.

Adenoma↗

PubMed2005

Lack of association between EBV and breast carcinoma.

Multiple conflicting findings have been presented which indicate that EBV may be found in anywhere from 0% to 51% of breast carcinomas. When EBV has been found causally associated with other human cancers, its DNA and one or more of its viral products have been detected in most tumor cells of a given biopsy. To test whether EBV has such an association with breast cancer, we measured the number of viral DNA molecules per cell in matched normal and tumor biopsies from 45 patients using real-time quantitative PCR. In no case could EBV DNA consistently be detected, with either of two different probes, at levels above 0.1 molecules per cell in two sections of the tumor samples. These levels of detection match those detected in EBV-negative cell lines and therefore likely represent noise in the assays. Equally importantly, the distribution of these low signals was the same between tumors and their matched normal controls. We conclude that EBV does not contribute to the development of breast cancers as it does to epithelial cancers such as nasopharyngeal and gastric carcinomas or to Burkitt's and Hodgkin's lymphomas.

Actins↗

PubMed2004

Detecting differential gene expression with a semiparametric hierarchical mixture method.

Mixture modeling provides an effective approach to the differential expression problem in microarray data analysis. Methods based on fully parametric mixture models are available, but lack of fit in some examples indicates that more flexible models may be beneficial. Existing, more flexible, mixture models work at the level of one-dimensional gene-specific summary statistics, and so when there are relatively few measurements per gene these methods may not provide sensitive detectors of differential expression. We propose a hierarchical mixture model to provide methodology that is both sensitive in detecting differential expression and sufficiently flexible to account for the complex variability of normalized microarray data. EM-based algorithms are used to fit both parametric and semiparametric versions of the model. We restrict attention to the two-sample comparison problem; an experiment involving Affymetrix microarrays and yeast translation provides the motivating case study. Gene-specific posterior probabilities of differential expression form the basis of statistical inference; they define short gene lists and false discovery rates. Compared to several competing methodologies, the proposed methodology exhibits good operating characteristics in a simulation study, on the analysis of spike-in data, and in a cross-validation calculation.

Algorithms↗

PubMed2004

Genetic determination of susceptibility to estrogen-induced mammary cancer in the ACI rat: mapping of Emca1 and Emca2 to chromosomes 5 and 18.

Hormonal, genetic, and environmental factors play major roles in the complex etiology of breast cancer. When treated continuously with 17beta-estradiol (E2), the ACI rat exhibits a genetically conferred propensity to develop mammary cancer. The susceptibility of the ACI rat to E2-induced mammary cancer appears to segregate as an incompletely dominant trait in crosses to the resistant Copenhagen (COP) strain. In both (ACI x COP)F(2) and (COP x ACI)F(2) populations, we find strong evidence for a major genetic determinant of susceptibility to E2-induced mammary cancer on distal rat chromosome 5. Our data are most consistent with a model in which the ACI allele of this locus, termed Emca1 (estrogen-induced mammary cancer 1), acts in an incompletely dominant manner to increase both tumor incidence and tumor multiplicity as well as to reduce tumor latency in these populations. We also find evidence suggestive of a second locus, Emca2, on chromosome 18 in the (ACI x COP)F(2) population. The ACI allele of Emca2 acts in a dominant manner to increase incidence and decrease latency. Together, Emca1 and Emca2 act independently to modify susceptibility to E2-induced mammary cancer.

Animals↗