Search PubMed⌕ Search
Home/Archive/PubMed

PubMed · 16015030

Linear parameter haplotype models with stratification.

T L Bergemann·D B Clarkson
View original source ↗Export metadata ↓

Abstract

OBJECTIVES: The question of interest is estimating the relationship between haplotypes and an outcome measure, based upon unphased genotypes. The outcome of interest might be predicting the presence of disease in a logistic model, predicting a numeric drug response in a linear model, or predicting survival time in a parametric survival model with censoring. Explanatory variables may include phased haplotype design variables, environmental variables, or interactions between them. METHODS: We extend existing generalized linear haplotype models to parametric survival outcomes. To improve the stability of model variance estimates, a profile likelihood solution is proposed. An adjustment for population stratification is also considered. Here we investigate data sampled from known 'strata' (e.g., gender or ethnicity) that influence haplotype prior probabilities and thus the regression model weights. Differing linear model variance estimates, and the effect of stratification and departures from Hardy-Weinberg Equilibrium (HWE) on parameter estimates, are compared and contrasted via simulation. RESULTS: From simulations, we observed an improvement in statistical power when using a solution to profile likelihood equations. We also saw that stratification had little impact on estimates. Haplotypes that are not in HWE had a negative impact on power to test hypotheses. Finally, profile likelihood solutions for haplotypes deviating from HWE had improved power and confidence interval coverage of regression model coefficients.

Explore related subjects

Carcinoma, Squamous CellComputer SimulationHaplotypesHumansLikelihood FunctionsModels, GeneticMouth NeoplasmsPolymorphism, Single NucleotideJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, U.S. Gov't, P.H.S.

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

T L Bergemann, D B Clarkson. 2005-07-07. Linear parameter haplotype models with stratification.. https://doi.org/10.1159/000086698

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2017

Nonpromoter methylation of the CDKN2A gene with active transcription is associated with improved locoregional control in laryngeal squamous cell carcinoma.

We previously reported a novel association between CDKN2A nonpromoter methylation and transcription (ARF/INK4a) in human papillomavirus associated oropharyngeal tumors. In this study we assessed whether nonpromoter CDKN2A methylation in laryngeal squamous cell carcinomas (LXSCC) conferred a similar association with transcription that predicted patient outcome. We compared DNA methylation and ARF/INK4a RNA expression levels for the CDKN2A locus using the Illumina HumanMethylation27 beadchip and RT-PCR in 43 LXSCC tumor samples collected from a prospective study of head and neck cancer patients treated at Montefiore Medical Center (MMC). Validation was performed using RNAseq data on 111 LXSCC tumor samples from the Cancer Genome Atlas (TCGA). The clinical relevance of combined nonpromoter CDKN2A methylation and transcription was assessed by multivariate Cox regression for locoregional recurrence on a subset of 69 LXSCC patients with complete clinicopathologic data from the MMC and TCGA cohorts. We found evidence of CDKN2A nonpromoter hypermethylation in a third of LXSCC from our MMC cohort, which was significantly associated with increased ARF and INK4a RNA expression (Wilcoxon rank-sum, P&#xa0;=&#xa0;0.007 and 0.003, respectively). A similar association was confirmed in TCGA samples (Wilcoxon rank-sum test P&#xa0;<&#xa0;0.0001 for ARF and INK4a). Patients with CDKN2A hypermethylation or high ARF/INK4a expression were significantly less likely to develop a locoregional recurrence compared to those with neither of the features, independent of other clinicopatholgic risk factors (adjusted hazard ratio=0.21, 95% confidence interval:0.05-0.81). These results support the conclusion that CDKN2A nonpromoter methylation is associated with increased ARF and INK4a RNA expression, and improved locoregional control in LXSCC.

Carcinoma, Squamous Cell↗
PubMed2006

Characterization of CD44v3-containing isoforms in head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is a debilitating and deadly disease that is only cured 50% of the time. A better understanding of the molecular mechanisms involved in HNSCC progression may lead to earlier detection and improved cure rates. CD44 is a ubiquitous transmembrane glycoprotein comprising a family of alternatively spliced isoforms involved in cell migration and cell proliferation. CD44 isoforms containing the variant 3 (v3) exon include a growth factor binding site and may be involved in tumor progression. To characterize CD44v3-containing isoforms expression in HNSCC we purified RNA from four HNSCC cell lines and performed RT-PCR using junction primer strategies followed by gel elecrophoresis. Cloning and sequencing of HNSCC cell line PCR products revealed two isoforms. One of these, CD44v3-10, has been previously described. The other isoform, CD44v3, has not been characterized in HNSCC tissues. To further study this isoform, we purified RNA from 19 HNSCC tissues, 7 normal margin tissues and 5 true normal tissues. Following reverse-transcription, we performed quantitative PCR using junction primers specific for CD44v3. Results show that HNSCC tumor tissues expressed mean CD44v3 levels that were elevated 4.5 times more than true normal tissues (p < 0.01). Mean CD44v3 values for HNSCC tumors were 0.43 +/- 0.44 while mean levels for true normal tissues were 0.10 +/- 0.11. Levels in tumor tissue did not vary significantly with tumor characteristics such as site, stage, prior treatment, or nodal status. In addition, to characterize the role of this molecule plays in tumor progression, we overexpressed CD44v3 in a HNSCC cell line. Our results indicate that although higher levels of CD44v3 did not affect the rate of proliferation, a significant increase in migration was observed. CD44v3 may provide a target for future diagnostic and therapeutic interventions for HNSCC.

Carcinoma, Squamous Cell↗
PubMed2006

Early supraglottic cancer: how extensive must surgical resection be, if used alone?

OBJECTIVES: Two centre based evaluations of oncologic results of endoscopic resection of supraglottic cancer without post-operative irradiation. PATIENTS AND METHODS: Twenty-six patients with clinical T1 (n=5) or T2 (n=21) primary squamous cell carcinomas of the supraglottic larynx and with N0 (n=24) or N1 (n=2) neck disease were treated by endoscopic supraglottic laryngectomy coupled with neck dissection(s). Endoscopic resection was standardized whereas neck dissections (NDs) varied from classical modified radical ND to selective ND of levels I to IV. RESULTS: Pathologically, three T2 patients were upstaged to T3, four N0 patients to N1 and one N2 patient down-staged to N1. Within an average of 42 months, there were no local failures and only one regional failure. CONCLUSIONS: Endoscopic resection of T1 and T2 supraglottic cancer without post-operative irradiation achieved good oncological results. No patients with lateralized primary cancers were found to have contralateral cancer on pathological evaluation from bilateral dissections.

Carcinoma, Squamous Cell↗