Biomedical subjects

Timothy P York

Publications and source records attributed to Timothy P York.

4 recordsLinked to original sources

PubMed2006

Multivariate adaptive regression splines: a powerful method for detecting disease-risk relationship differences among subgroups.

In a wide variety of medical research scenarios one is interested in the question whether regression curves differ for subgroups in the sample. Examples are gender differences in the effect of drug treatment or the study of genotype-environment interactions. To address this question exploratory techniques are often required because detailed knowledge concerning the shape of the regression curves and how that shape differs across subgroups is lacking. In this article we explored the power of two such exploratory techniques: multivariate adaptive regression splines (MARS) and least squares curve fitting using polynomials. For this purpose simulations were performed using linear, logistic, and complex non-linear curves. The power obtained from MARS was on average 1.4 times higher than with polynomials. It was shown that power was higher even if the regression curve was linear, that gains increased with the complexity of the curve, and that for highly non-linear curves model-free methods such as MARS might be the only alternative.

Biometry↗

PubMed2005

cDNA microarray analysis identifies genes induced in common by peptide growth factors and androgen in human prostate epithelial cells.

Prostate cancer cells initially require androgen for continued proliferation, but invariably become androgen independent or unresponsive and recur after treatment by androgen ablation. Exploitation of common signaling components downstream of their specific receptors (i.e., androgen receptor (AR), insulin-like growth factor 1 (IGF-1) receptor, and epidermal growth factor (EGF) receptor) could provide a mechanism by which androgen independent cells survive and proliferate. Our objective was to design and implement prostate enriched cDNA microarrays to identify genes induced in prostate epithelial cells in a similar temporal pattern by both androgen and IGF or EGF. AR positive and AR negative human prostate epithelial cells of the M12 line were exposed in parallel to DHT, EGF, or IGF for 0, 6, or 24 h. RNA extracted from each of these groups was analyzed by cDNA microarrays composed of a unique set of 6373 prostate-derived cDNA clones from the Prostate Expression Database (PEDB). We observed statistically significant changes in 20 genes induced in common after 6 and 24 h exposure to androgen or these growth factors, and validated the microarray results by RT-PCR for three or four of these genes: v-myc, isocitrate dehydrogenase, and calnexin. Androgen response element binding motifs were identified in the upstream sequence in 16 of these 20 genes. These results provide comprehensive and unique insights into potential mechanisms by which peptide growth factors provide alternate pathways to control prostate epithelial cell proliferation in malignant states.

Biomarkers, Tumor↗

PubMed2005

Epistatic and environmental control of genome-wide gene expression.

All etiological studies of complex human traits focus on analyzing the causes of variation. Given this complexity, there is a premium on studying those processes that mediate between gene products and cellular or organismal phenotypes. Studies of levels of gene expression could offer insight into these processes and are likely to be especially useful to the extent that the major sources of their variation are known in normal tissues. The classical study of monozygotic (MZ) and dizygotic (DZ) twins was employed to partition the genetic and environmental influences in gene expression for over 6500 human genes measured using microarrays from lymphoblastoid cell lines. Our results indicate that mean expression levels are correlated about .3 in monozygotic (MZ) and .0 in dizygotic (DZ) twins suggesting an overall epistatic regulation of gene expression. Furthermore, the functions of several of the genes whose expression was most affected by environmental effects, after correction for measurement error, were consistent with their known role in mediating sensitivity to environmental influences.

Adolescent↗

PubMed2004

Genomewide analysis of gene expression associated with Tcof1 in mouse neuroblastoma.

Mutations in the Treacher Collins syndrome gene, TCOF1, cause a disorder of craniofacial development. We manipulated the levels of Tcof1 and its protein treacle in a murine neuroblastoma cell line to identify downstream changes in gene expression using a microarray platform. We identified a set of genes that have similar expression with Tcof1 as well as a set of genes that are negatively correlated with Tcof1 expression. We also showed that the level of Tcof1 and treacle expression is downregulated during differentiation of neuroblastoma cells into neuronal cells. Inhibition of Tcof1 expression by siRNA induced morphological changes in neuroblastoma cells that mimic differentiation. Thus, expression of Tcof1 and treacle synthesis play an important role in the proliferation of neuroblastoma cells and we have identified genes that may be important in this pathway.

Animals↗