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Shelley B Bull

Publications and source records attributed to Shelley B Bull.

At least 19 recordsLinked to original sources

Confidence intervals for multinomial logistic regression in sparse data.

Logistic regression is one of the most widely used regression models in practice, but alternatives to conventional maximum likelihood estimation methods may be more appropriate for small or sparse samples. Modification of the logistic regression score function to remove first-order bias is equivalent to penalizing the likelihood by the Jeffreys prior, and yields penalized maximum likelihood estimates (PLEs) that always exist, even in samples in which maximum likelihood estimates (MLEs) are infinite. PLEs are an attractive alternative in small-to-moderate-sized samples, and are preferred to exact conditional MLEs when there are continuous covariates. We present methods to construct confidence intervals (CI) in the penalized multinomial logistic regression model, and compare CI coverage and length for the PLE-based methods to that of conventional MLE-based methods in trinomial logistic regressions with both binary and continuous covariates. Based on simulation studies in sparse data sets, we recommend profile CIs over asymptotic Wald-type intervals for the PLEs in all cases. Furthermore, when finite sample bias and data separation are likely to occur, we prefer PLE profile CIs over MLE methods.

Aspartate Aminotransferases↗

Type of TP53 mutation and ERBB2 amplification affects survival in node-negative breast cancer.

Alterations of TP53 and ERBB2 have been shown to play important roles in the prognosis of breast cancer. The primary objective of this study is to characterize TP53 mutation types in node negative breast cancer and investigate their prognostic value, alone and in combination with ERBB2 amplification status. TP53 mutational status (exons 2-10) and ERBB2 amplification status were determined in tumor specimens from a prospective cohort of 543 women with node-negative breast cancer. During a median follow-up of 120 months, there were 111 disease recurrences, and 81 disease-related deaths (3 with cancer; 78 from cancer). Of 543 women, 133 (24.5%) carried mutations in exons 4-9 of the TP53 gene. Seventy-one (53.4%) of these mutations were missense; whereas 62 (46.6%) were protein-truncating mutations. Women whose tumors had missense TP53 mutations were found to be at significantly higher risk of recurrence and death compared to those with wild type TP53, and they also tended to have worse prognosis compared to those with truncating mutations. Those with short truncated proteins tended to have good prognosis compared to those with long truncated proteins, but the risk of recurrence and death did not differ between those whose tumors exhibited conserved versus non-conserved mutations. Missense mutations, in combination with ERBB2 amplification, were observed in 4.6% of the tumors and dramatically affected the disease-specific survival (DSS) and disease-free survival (DFS) of the breast cancer patients. Our study suggests that the type of TP53 mutation, especially missense mutation, is a strong prognostic indicator for DFS and DSS in node-negative breast cancer, particularly in combination with ERBB2 amplification.

Breast Neoplasms↗

A hierarchical clustering method for estimating copy number variation.

Microarray technologies allow for simultaneous measurement of DNA copy number at thousands of positions in a genome. Gains and losses of DNA sequences reveal themselves through characteristic patterns of hybridization intensity. To identify change points along the chromosomes, we develop a marker clustering method which consists of 2 parts. First, a "circular clustering tree test statistic" attaches a statistic to each marker that measures the likelihood that it is a change point. Then construction of the marker statistics is followed by outlier detection approaches. The method provides a new way to build up a binary tree that can accurately capture change-point signals and is easy to perform. A simulation study shows good performance in change-point detection, and cancer cell line data are used to illustrate performance when regions of true copy number changes are known.

Algorithms↗

Locus-specific heritability estimation via the bootstrap in linkage scans for quantitative trait loci.

BACKGROUND/AIMS: In genome-wide linkage analysis of quantitative trait loci (QTL), locus-specific heritability estimates are biased when the original data are used to both localize linkage and estimate effects, due to maximization of the LOD score over the genome. Positive bias is increased by adoption of stringent significance levels to control genome-wide type I error. We propose multi-locus bootstrap resampling estimators for bias reduction in the situation in which linkage peaks at more than one QTL are of interest. METHODS: Bootstrap estimates were based on repeated sample splitting in the original dataset. We conducted simulation studies in nuclear families with 0 to 5 QTLs and applied the methods in a genome-wide analysis of a blood pressure phenotype in extended pedigrees from the Framingham Heart Study (FHS). RESULTS: Compared to naïve estimates in the original simulation samples, bootstrap estimates had reduced bias and smaller mean squared error. In the FHS pedigrees, the bootstrap yielded heritability estimates as much as 70% smaller than in the original sample. CONCLUSIONS: Because effect estimates obtained in an initial study are typically inflated relative to those expected in an independent replication study, successful replication will be more likely when sample size requirements are based on bias-reduced estimates.

Cardiovascular Diseases↗

High urinary calcium excretion and genetic susceptibility to hypertension and kidney stone disease.

Increased urinary calcium excretion commonly is found in patients with hypertension and kidney stone disease (KSD). This study investigated the aggregation of hypertension and KSD in families of patients with KSD and hypercalciuria and explored whether obesity, excessive weight gain, and diabetes, commonly related conditions, also aggregate in these families. Consecutive patients with KSD, aged 18 to 50 yr, were recruited from a population-based Kidney Stone Center, and a 24-h urine sample was collected. The first-degree relatives of eligible patients (n = 333) and their spouse were interviewed by telephone to collect demographic and health information. Familial aggregation was assessed using generalized estimating equations. Multivariate-adjusted odds ratios (OR) revealed significant associations between hypercalciuria in patients and hypertension (OR 2.9; 95% confidence interval 1.4 to 6.2) and KSD (OR 1.9; 95% confidence interval 1.03 to 3.5) in first-degree relatives, specifically in siblings. No significant associations were found in parents or spouses or in patients with hyperuricosuria. Similarly, no aggregation with other conditions was observed. In an independent study of siblings of hypercalciuric patients with KSD, the adjusted mean fasting urinary calcium/creatinine ratio was significantly higher in the hypertensive siblings compared with normotensive siblings (0.60 +/- 0.32 versus 0.46 +/- 0.28 mmol/mmol; P < 0.05), and both sibling groups had significantly higher values than the unselected study participants (P < 0.001). Urinary sodium/creatinine and uric acid/creatinine ratios were not different among the groups. Although an environmental effect cannot be excluded fully, our findings suggest that the disturbance in calcium metabolism in hypertension and KSD has a genetic basis.

Adolescent↗

Application of reliability coefficients in cDNA microarray data analysis.

Gene expression microarray technology has been widely used in areas such as human cancer research to identify molecular characteristics of sample specimens. The microarray study, however, is a very complicated procedure which involves numerous sources of variability that may be either systematic or random. Systematic variation is often eliminated by applying normalization procedures, but at present there are no standard criteria available to evaluate the performance of a particular normalization approach. In this paper, we propose a reliability-type coefficient as a criterion to assess the effectiveness of normalization procedures in eliminating systematic variation. Simulation studies show that this criterion performs reasonably well in a range of settings. The proposed method is illustrated using a subset of an ongoing microarray study of soft-tissue sarcoma.

Computer Simulation↗

Genomic alterations in lobular neoplasia: a microarray comparative genomic hybridization signature for early neoplastic proliferationin the breast.

The identification of genomic alterations occurring in neoplastic lesions provides insight into both lesion occurrence and disease progression. In this study, we used microarray comparative genomic hybridization (CGH) to investigate genetic changes in atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), as the presence of these lobular neoplastic lesions is an indicator of risk in the development of invasive breast cancer. DNA was extracted from microdissected archival breast tissue containing ALH or LCIS, lacking adjacent invasive carcinoma, and subjected to whole-genome tiling path microarray-CGH using the submegabase resolution tiling set (SMRT)-array platform. Twelve ALH and 13 LCIS lesions were examined. Copy number alterations were identified using statistical criteria and validated with Real-Time PCR and fluorescence in situ hybridization. From statistical analysis, a greater number of alterations were observed in ALH compared to LCIS. Alterations common to ALH include gain at 2p11.2 and loss at 7p11-p11.1 and 22q11.1. Alterations common to LCIS include gain at 20q13.13 and loss at 19q13.2-q13.31. In both ALH and LCIS, we observed loss of 16q21-q23.1, an altered region previously identified in lobular neoplasia and invasive carcinoma. The validation of select alterations reinforces the genomic signature. This study represents the first whole-genome investigation of lobular neoplastic breast lesions using clinical archival specimens. The identified genomic signature includes copy number alterations not previously identified for lobular neoplasia. This genomic signature, common to ALH and LCIS, suggests a role for the acquisition of novel genomic alterations in the aberrant cellular proliferation that defines lobular neoplasia.

Breast Neoplasms↗

Validity, efficiency, and robustness of a family-based test of association.

We propose a new test of linkage in the presence of allelic association that uses all available information in a sample of nuclear families, including parental phenotypes, genotypes from both affected and unaffected siblings, and families with homozygous parents. The test is based on the conditional framework developed by Rabinowitz and Laird [2000: Hum Hered 50:211-223] and is thus immune to population stratification and can be applied to families with any pattern of missing information. The test statistic is a conditional likelihood ratio based on a standard two-point linkage model with allelic association, where parameters are estimated from the sample. Through a simulation study, we determined that the proposed test has near optimal power for a wide range of scenarios, outperforming FBAT both when data were complete and when parental genotypes were missing, although differences between the two tests diminish as the genetic effect is reduced. To assess robustness, we also evaluated the performance of the tests under scenarios with population stratification and found that although there is a loss of efficiency, our proposed test remains a strong competitor to FBAT.

Alleles↗

Stratified false discovery control for large-scale hypothesis testing with application to genome-wide association studies.

The multiplicity problem has become increasingly important in genetic studies as the capacity for high-throughput genotyping has increased. The control of False Discovery Rate (FDR) (Benjamini and Hochberg. [1995] J. R. Stat. Soc. Ser. B 57:289-300) has been adopted to address the problems of false positive control and low power inherent in high-volume genome-wide linkage and association studies. In many genetic studies, there is often a natural stratification of the m hypotheses to be tested. Given the FDR framework and the presence of such stratification, we investigate the performance of a stratified false discovery control approach (i.e. control or estimate FDR separately for each stratum) and compare it to the aggregated method (i.e. consider all hypotheses in a single stratum). Under the fixed rejection region framework (i.e. reject all hypotheses with unadjusted p-values less than a pre-specified level and then estimate FDR), we demonstrate that the aggregated FDR is a weighted average of the stratum-specific FDRs. Under the fixed FDR framework (i.e. reject as many hypotheses as possible and meanwhile control FDR at a pre-specified level), we specify a condition necessary for the expected total number of true positives under the stratified FDR method to be equal to or greater than that obtained from the aggregated FDR method. Application to a recent Genome-Wide Association (GWA) study by Maraganore et al. ([2005] Am. J. Hum. Genet. 77:685-693) illustrates the potential advantages of control or estimation of FDR by stratum. Our analyses also show that controlling FDR at a low rate, e.g. 5% or 10%, may not be feasible for some GWA studies.

Chromosome Mapping↗

Analysis of incidence and prognostic factors for ipsilateral breast tumour recurrence and its impact on disease-specific survival of women with node-negative breast cancer: a prospective cohort study.

INTRODUCTION: This study had three aims: to establish the incidence of ipsilateral breast tumour recurrence (IBTR) in a community treatment setting, to evaluate known factors--in particular younger age (< 40 years)--predictive for local recurrence, and to assess the impact of local recurrence on disease-specific survival (DSS). METHODS: A consecutive series of 1,540 women with node-negative breast cancer, diagnosed between the ages of 18-75 years, were prospectively accrued between September 1987 and September 1999. All had undergone a resection of the primary breast cancer with clear margins, an axillary lymph node dissection with a minimum of four sampled nodes, and breast-conserving surgery (of any type). RESULTS: During the study follow-up period, 98 (6.4%) IBTRs and 117 (7.6%) deaths from or with breast cancer were observed. The median time to IBTR was 3.1 years and to death from or with disease was 4.3 years. In the multivariate Cox proportional hazards (PH) regression model for IBTR with adjuvant therapy factors, independent risk factors included age < 40 years (relative risk (RR) = 1.89, 95% confidence interval (CI) of 1.00 - 3.58), presence of intraductal disease (RR = 1.81, 95% CI = 1.15-2.85) and histological grade ('G2' or G3 versus G1: RR = 1.59, 95% CI = 0.87-2.94). In the multivariate Cox PH regression model for DSS with adjuvant therapy factors, independent risk factors included previous IBTR (RR = 2.58, 95% CI = 1.41-4.72), tumor size (1-2 cm versus < 1 cm: RR = 1.95, 95% CI = 1.05-3.64, > 2 cm versus < 1 cm: RR = 2.94, 95% CI = 1.56-5.56), progesterone receptor status (negative or equivocal versus positive or unknown: RR = 2.15, 95% CI = 1.36-3.39), lymphatic invasion (RR = 1.78, 95% CI = 1.17-2.72), and histological grade ('G2' or G3 versus G1: RR = 8.59, 95% CI = 2.09-35.36). The effects of competing risks could be ignored. CONCLUSION: The Cox PH analyses confirmed the importance of known risk factors for IBTR and DSS in a community treatment setting. This study also revealed that the early occurrence of an IBTR is associated with a relatively poor five-year survival rate.

Adolescent↗

Resampling methods to reduce the selection bias in genetic effect estimation in genome-wide scans.

Using the simulated data of Problem 2 for Genetic Analysis Workshop 14 (GAW14), we investigated the ability of three bootstrap-based resampling estimators (a shrinkage, an out-of-sample, and a weighted estimator) to reduce the selection bias for genetic effect estimation in genome-wide linkage scans. For the given marker density in the preliminary genome scans (7 cM for microsatellite and 3 cM for SNP), we found that the two sets of markers produce comparable results in terms of power to detect linkage, localization accuracy, and magnitude of test statistic at the peak location. At the locations detected in the scan, application of the three bootstrap-based estimators substantially reduced the upward selection bias in genetic effect estimation for both true and false positives. The relative effectiveness of the estimators depended on the true genetic effect size and the inherent power to detect it. The shrinkage estimator is recommended when the power to detect the disease locus is low. Otherwise, the weighted estimator is recommended.

Chromosome Mapping↗

Recursive partitioning models for linkage in COGA data.

We have developed a recursive-partitioning (RP) algorithm for identifying phenotype and covariate groupings that interact with the evidence for linkage. This data-mining approach for detecting gene x environment interactions uses genotype and covariate data on affected relative pairs to find evidence for linkage heterogeneity across covariate-defined subgroups. We adapted a likelihood-ratio based test of linkage parameterized with relative risks to a recursive partitioning framework, including a cross-validation based deviance measurement for choosing optimal tree size and a bootstrap sampling procedure for choosing robust tree structure. ALDX2 category 5 individuals were considered affected, categories 1 and 3 unaffected, and all others unknown. We sampled non-overlapping affected relative pairs from each family; therefore, we used 144 affected pairs in the RP model. Twenty pair-level covariates were defined from smoking status, maximum drinks, ethnicity, sex, and age at onset. Using the all-pairs score in GENEHUNTER, the nonparametric linkage tests showed no regions with suggestive linkage evidence. However, using the RP model, several suggestive regions were found on chromosomes 2, 4, 6, 14, and 20, with detection of associated covariates such as sex and age at onset.

Alcoholism↗

Comparison of family-based association tests in chromosome regions selected by linkage-based confidence intervals.

We use the Genetic Analysis Workshop 14 simulated data to explore the effectiveness of a two-stage strategy for mapping complex disease loci consisting of an initial genome scan with confidence interval construction for gene location, followed by fine mapping with family-based tests of association on a dense set of single-nucleotide polymorphisms. We considered four types of intervals: the 1-LOD interval, a basic percentile bootstrap confidence interval based on the position of the maximum Zlr score, and asymptotic and bootstrap confidence intervals based on a generalized estimating equations method. For fine mapping we considered two family-based tests of association: a test based on a likelihood ratio statistic and a transmission-disequilibrium-type test implemented in the software FBAT. In two of the simulation replicates, we found that the bootstrap confidence intervals based on the peak Zlr and the 1-LOD support interval always contained the true disease loci and that the likelihood ratio test provided further strong confirmatory evidence of the presence of disease loci in these regions.

Chromosomes, Human↗

TP53 mutations and outcome in osteosarcoma: a prospective, multicenter study.

PURPOSE: Mutations of the TP53 gene have been associated with resistance to chemotherapy as well as poor prognosis in many different malignancies. This is the first prospective study of the prognostic value of somatic TP53 mutations in patients with newly diagnosed extremity osteosarcoma. PATIENTS AND METHODS: One hundred ninety-six patients with high-grade, nonmetastatic osteosarcoma of the extremities were enrolled from seven tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 44 months). All patients received neoadjuvant or adjuvant chemotherapy and surgery. Tumors were analyzed for the presence of TP53 mutations by polymerase chain reaction single-strand conformation polymorphism analysis and direct DNA sequencing. The association of the status of the TP53 gene with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors. RESULTS: Patient age was the only factor that varied with TP53 gene status (P = .05). No relationship was identified between TP53 status and systemic relapse (relative risk, 1.24; P = .41). Analyses based on missense or nonsense mutations gave similar results (P > .10). In multivariate analysis, large (> 9 cm) tumor size (relative risk, 1.9; P = .006) and poor histologic response (< or = 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome. CONCLUSION: We found no evidence that TP53 mutations predict for development of metastases in patients with high-grade osteosarcoma. Identification of other genes that influence chemotherapy response and clinical outcome in osteosarcoma is needed to facilitate further improvements in patient outcomes.

Adolescent↗

Simultaneous localization of two linked disease susceptibility genes.

For diseases with complex genetic etiology, more than one susceptibility gene may exist in a single chromosomal region. Extending the work of Liang et al. ([2001] Hum. Hered. 51:64-78), we developed a method for simultaneous localization of two susceptibility genes in one region. We derived an expression for expected allele sharing of an affected sib pair (ASP) at each point across a chromosomal segment containing two susceptibility genes. Using generalized estimating equations (GEE), we developed an algorithm that uses marker identical-by-descent (IBD) sharing in affected sib pairs to simultaneously estimate the locations of the two genes and the mean IBD sharing in ASPs at these two disease loci. Confidence intervals for gene locations can be constructed based on large sample approximations. Application of the described methods to data from a genome scan for type 1 diabetes (Mein et al. [1998] Nat. Genet. 19:297-300) yielded estimates of two putative disease gene locations on chromosome 6, approximately 20 cM apart. Properties of the estimators, including bias, precision, and confidence interval coverage, were studied by simulation for a range of genetic models. The simulations demonstrated that the proposed method can improve disease gene localization and aid in resolving large peaks when two disease genes are present in one chromosomal region. Joint localization of two disease genes improves with increased excess allele sharing at the disease gene loci, increased distance between the disease genes, and increased number of affected sib pairs in the sample.

Algorithms↗

Reduction of selection bias in genomewide studies by resampling.

The accuracy of gene localization, the reliability of locus-specific effect estimates, and the ability to replicate initial claims of linkage and/or association have emerged as major methodological concerns in genomewide studies of complex diseases and quantitative traits. To address the issue of multiple comparisons inherent in genomewide studies, the use of stringent criteria for assessing statistical significance has been generally acknowledged as a strategy to control type I error. However, the application of genomewide significance criteria does not take account of the selection bias introduced into parameter estimates, e.g., estimates of locus-specific effect size of disease/trait loci. Some have argued that reliable locus-specific parameter estimates can only be obtained in an independent sample. In this report, we examine statistical resampling techniques, including cross-validation and the bootstrap, applied to the initial sample to improve the estimation of locus-specific effects. We compare them with the naive method in which all data are used for both hypothesis testing and parameter estimation, as well as with the split-sample approach in which part of the data are reserved for estimation. Upward bias of the naive estimator and inadequacy of the split-sample approach are derived analytically under a simple quantitative trait model. Simulation studies of the resampling methods are performed for both the simple model and a more realistic genomewide linkage analysis. Our results suggest that cross-validation and bootstrap methods can substantially reduce the estimation bias, especially when the effect size is small or there is no genetic effect.

Algorithms↗

Tests for the presence of two linked disease susceptibility genes.

For diseases with complex genetic etiology, more than one susceptibility gene may exist in a single chromosomal region. Under explicit assumptions about the number of disease genes in a region, generalized estimating equations (GEE) can be used to estimate the putative disease gene location(s) and expected identical-by-descent allele sharing in affected sib pairs at these gene(s). Extending the work of Liang et al. developed a method for simultaneous localization of two susceptibility genes in one region using marker identical-by-descent (IBD) sharing in affected sib pairs. Here we propose methods to evaluate the evidence for two versus one disease loci in a region in a quasi-likelihood/GEE framework. We describe tests based on approximate quasi-likelihood ratio and generalized score test statistics. Because of difficulties in determining the asymptotic null distributions of these statistics and the small sample sizes that can be available in genetic studies, we recommend that significance be evaluated empirically. Application of the described methods to data from a genome scan for type 1 diabetes yielded some evidence for two linked disease genes on chromosome 6, approximately 20 cM apart (p value for an approximate quasi-likelihood ratio test=0.049). In simulation studies, we found that both tests performed quite well for a range of scenarios. Power to detect the presence of two linked disease genes increased with the number of affected sib pairs, greater IBD sharing at the two loci, and larger distance between the two loci.

Diabetes Mellitus, Type 1↗

Fine mapping by linkage and association in nuclear family and case-control designs.

This report summarizes the Genetic Analysis Workshop 14 contributions related to fine-mapping strategies, in which examining smaller regions by association with single-nucleotide polymorphisms (SNPs) can yield savings in genotyping and multiple-testing penalties. The aim of the analyses conducted in Group 7 contributions was to localize disease susceptibility loci from either the simulated or the Collaborative Study on the Genetics of Alcoholism (COGA) data within identified regions of linkage. Among the 10 contributions, most groups analyzed the simulated data, one group analyzed the COGA data only, and one group analyzed both data sets. The research questions included evaluation of new methods of analysis, as well as comparisons among alternative methods, analytic strategies, and study designs. Methods of interest included an algorithm for SNP marker ordering, a locally weighted transmission disequilibrium test statistic, a likelihood-ratio test statistic for family-based association in nuclear families, a robust test statistic for case-control association studies, and Bayesian spatial modeling methods for haplotype clustering and association. Evaluations included comparisons among confidence intervals for loci detected via linkage, effects of multiple testing adjustments and trade-offs between type I error and power, comparisons among haplotype-based (multilocus) and genotype-based (multilocus and single-locus) association analyses, and design of fine-mapping and replication studies. While several promising new approaches were identified, further development and evaluation of methods for multiple testing, regression modeling of association with multiple markers and haplotypes, and combined treatment of linkage and association data are necessary if we are to identify many of the genes that contribute to complex traits.

Alcoholism↗