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At least 487 records · Page 27Linked to original sources
PubMed2006

Assessing stability of gene selection in microarray data analysis.

BACKGROUND: The number of genes declared differentially expressed is a random variable and its variability can be assessed by resampling techniques. Another important stability indicator is the frequency with which a given gene is selected across subsamples. We have conducted studies to assess stability and some other properties of several gene selection procedures with biological and simulated data. RESULTS: Using resampling techniques we have found that some genes are selected much less frequently (across sub-samples) than other genes with the same adjusted p-values. The extent to which this type of instability manifests itself can be assessed by a method introduced in this paper. The effect of correlation between gene expression levels on the performance of multiple testing procedures is studied by computer simulations. CONCLUSION: Resampling represents a tool for reducing the set of initially selected genes to those with a sufficiently high selection frequency. Using resampling techniques it is also possible to assess variability of different performance indicators. Stability properties of several multiple testing procedures are described at length in the present paper.

Biomarkers, Tumor↗
PubMed2006

Tests for differential gene expression using weights in oligonucleotide microarray experiments.

BACKGROUND: Microarray data analysts commonly filter out genes based on a number of ad hoc criteria prior to any high-level statistical analysis. Such ad hoc approaches could lead to conflicting conclusions with no clear guidance as to which method is most likely to be reproducible. Furthermore, the number of tests performed with concomitant inflation in type I error also plagues the statistical analysis of microarray data, since the number of tested quantities in a study significantly affects the family-wise error rate. It would, therefore, be very useful to develop and adopt strategies that allow quantification of the quality of each probeset, to filter out or give little credence to low-quality or unexpressed probesets, and to incorporate these strategies into gene selection within a multiple testing framework. RESULTS: We have proposed a unified scheme for filtering and gene selection. For Affymetrix gene expression microarrays, we developed new methods for measuring the reliability of a particular probeset in a single array, and we used these to develop measures for a set of arrays. These measures are then used as weights in standard t-statistic calculations, and are incorporated into the multiple testing procedures. We demonstrated the advantages of our methods using simulated data, publicly available spiked-in data as well as data comparing normal muscle to muscle from patients with Duchenne muscular dystrophy (DMD), in which a set of truly differentially expressed genes is known. CONCLUSION: Our quality measures provide convenient ways to search for individual genes of high quality. The quality weighting strategies we proposed for testing differential gene expression have demonstrable improvement on the traditional filtering methods, the standard t-statistic and a regularized t-statistic in Affymetrix data analysis.

Data Interpretation, Statistical↗
PubMed2006

Using linkage genome scans to improve power of association in genome scans.

Scanning the genome for association between markers and complex diseases typically requires testing hundreds of thousands of genetic polymorphisms. Testing such a large number of hypotheses exacerbates the trade-off between power to detect meaningful associations and the chance of making false discoveries. Even before the full genome is scanned, investigators often favor certain regions on the basis of the results of prior investigations, such as previous linkage scans. The remaining regions of the genome are investigated simultaneously because genotyping is relatively inexpensive compared with the cost of recruiting participants for a genetic study and because prior evidence is rarely sufficient to rule out these regions as harboring genes with variation of conferring liability (liability genes). However, the multiple testing inherent in broad genomic searches diminishes power to detect association, even for genes falling in regions of the genome favored a priori. Multiple testing problems of this nature are well suited for application of the false-discovery rate (FDR) principle, which can improve power. To enhance power further, a new FDR approach is proposed that involves weighting the hypotheses on the basis of prior data. We present a method for using linkage data to weight the association P values. Our investigations reveal that if the linkage study is informative, the procedure improves power considerably. Remarkably, the loss in power is small, even when the linkage study is uninformative. For a class of genetic models, we calculate the sample size required to obtain useful prior information from a linkage study. This inquiry reveals that, among genetic models that are seemingly equal in genetic information, some are much more promising than others for this mode of analysis.

Genetic Linkage↗
PubMed1996

Permutation tests for multiple loci affecting a quantitative character.

The problem of detecting minor quantitative trait loci (QTL) responsible for genetic variation not explained by major QTL is of importance in the complete dissection of quantitative characters. Two extensions of the permutation-based method for estimating empirical threshold values are presented. These methods, the conditional empirical threshold (CET) and the residual empirical threshold (RET), yield critical values that can be used to construct tests for the presence of minor QTL effects while accounting for effects of known major QTL. The CET provides a completely nonparametric test through conditioning on markers linked to major QTL. It allows for general nonadditive interactions among QTL, but its practical application is restricted to regions of the genome that are unlinked to the major QTL. The RET assumes a structural model for the effect of major QTL, and a threshold is constructed using residuals from this structural model. The search space for minor QTL is unrestricted, and RET-based tests may be more powerful than the CET-based test when the structural model is approximately true.

Alleles↗
PubMed1997

Testing for treatment differences with dropouts present in clinical trials--a composite approach.

A major problem in the analysis of clinical trials is missing data from patients who drop out of the study before the predetermined schedule. In this paper we consider the situation where the outcome measure is a continuous variable and the final outcome at the end of the study is the main interest. We argue that the hypothetical complete-data marginal mean averaged over the dropout patterns is not as relevant clinically as the conditional mean of the completers together with the probability of completion or dropping out of the trial. We first take the pattern-mixture modelling approach to factoring the likelihood function, then direct the analysis to the multiple testings of a composite of hypotheses that involves the probability of dropouts and the conditional mean of the completers. We review three types of closed step-down multiple-testing procedures for this application. Data from several clinical trials are used to illustrate the proposed approach.

Bias↗
PubMed2000

Multiple comparisons in carcinogenesis study with right-censored survival data.

This paper considers the practical problem in animal carcinogenesis experiments where several treatment groups are compared with a control group in a one-way layout and the observed survival data are subject to random right-censorship. Proposed herein are multiple testing procedures based on two-sample weighted logrank statistics, each comparing an individual treatment with the control, for determining which treatments are more effective than the control. The associated p-value of claiming a certain treatment is more effective than the control is also discussed. A test-based confidence set for the scale changes between each treatment and the control is then obtained. The comparative results of a Monte Carlo error rate and power study for small sample sizes are presented. Finally, a numerical example involving renal carcinoma in mice demonstrates the feasibility of the proposed multiple testing procedures and test-based confidence set.

Animals↗
PubMed2005

Association Cluster Detector: a tool for heuristic detection of significance clusters in whole-genome scans.

UNLABELLED: Whole genome scans analyze large sets of genetic markers, mainly single nucleotide polymorphisms, over the entire genome in order to find variants and regions associated with complex traits so these can be further investigated. Analyzing the results of such scans becomes difficult due to multiple testing problems and to the genomic distributions of recombination, linkage disequilibrium and true associations, which generate an extremely complex network of dependences between markers. Here we present Association Cluster Detector (ACD), a simple tool aiming to ease the analysis of the results of whole genome scans. ACD facilitates correction for multiple tests using several standard procedures and implements a sliding-window heuristic method that helps in detecting potentially interesting candidate regions by exploiting the property of non-random distribution of significantly associated markers. AVAILABILITY: The tool can be downloaded from http://www.upf.es/cexs/recerca/bioevo/softanddata.htm

Algorithms↗
PubMed1995

Molecular tools for presymptomatic testing in multiple endocrine neoplasia type 1.

The aim of this workshop session was to define a set of molecular tools for pre-clinical diagnosis in affected families, and to assess presence or absence of linkage to 11q13 in families with classical MEN1 as well as with MEN1-related clinical features. A consensus linkage map of first- and second-choice markers based on PCR as well as Southern blotting was established at the workshop. Based on the results from linkage analysis in 87 families with classical MEN1, presymptomatic testing using the suggested panel of markers, can now be performed with great accuracy.

Acromegaly↗
PubMed1996

False-positive error rates in routine application of repeated measurements ANOVA.

Failure to recognize the serious implications of heterogeneous correlations and disregard of the multiple test problem in interpreting the results from repeated measurements ANOVA of any single primary outcome measure can produce false-positive error rates that are more than five times the alpha level that is reported. Alternative analyses that do not depend on the symmetry assumption, together with a Bonferroni correction of the multiple tests of significance that are routinely accomplished by the repeated measurements ANOVA, appropriately control the probability of statistical support for a false-positive claim. The magnitudes of error inflation and appropriate procedures for error control are examined in this article using simulated clinical trials data.

Analysis of Variance↗
PubMed2005

Will the real disease gene please stand up?

A common dilemma arising in linkage studies of complex genetic diseases is the selection of positive signals, their follow-up with association studies and discrimination between true and false positive results. Several strategies for overcoming these issues have been devised. Using the Genetic Analysis Workshop 14 simulated dataset, we aimed to apply different analytical approaches and evaluate their performance in discerning real associations. We considered a) haplotype analyses, b) different methods adjusting for multiple testing, c) replication in a second dataset, and d) exhaustive genotyping of all markers in a sufficiently powered, large sample group. We found that haplotype-based analyses did not substantially improve over single-point analysis, although this may reflect the low levels of linkage disequilibrium simulated in the datasets provided. Multiple testing correction methods were in general found to be over-conservative. Replication of nominally positive results in a second dataset appears to be less stringent, resulting in the follow-up of false positives. Performing a comprehensive assay of all markers in a large, well-powered dataset appears to be the most effective strategy for complex disease gene identification.

Chromosome Mapping↗
PubMed1998

Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians.

The K+ inwardly rectifier channel (KIR) is one of the two sub-units of the pancreatic islet ATP-sensitive potassium channel complex (I(KATP)), which has a key role in glucose-stimulated insulin secretion and thus is a potential candidate for a genetic defect in Type II (non-insulin-dependent) diabetes mellitus. We did a molecular screening of the KIR6.2 gene by single strand conformational polymorphism (SSCP) and direct sequencing in 72 French Caucasian Type II diabetic families. We identified three nucleotide substitutions resulting in three amino acid changes (E23K, L270V and 1337V), that have also been identified in other Caucasian Type II diabetic subjects. These variants were genotyped in French cohorts of 191 unrelated Type II diabetic probands and 119 normoglycaemic control subjects and association studies were done. The genotype frequencies of the L270V and 1337V variants were not very different between Type II diabetic subjects and control groups. In contrast, analysis of the E23K variant showed that the KK homozygocity was more frequent in Type II diabetic than in control subjects (27 vs 14%, p = 0.015). Analyses in a recessive model (KK vs EK/EE) tended to show a stronger association of the K allele with diabetes (p = 0.0097, corrected p-value for multiple testing < 0.02). The data for the E23K variant obtained here and those obtained from three other Caucasian groups studied so far were combined and investigated by meta-analysis. Overall, the E23K variant was found to be significantly associated with Type II diabetes (0.001 < or = p < or = .00106, corrected p-values for multiple testing p < or = 0.01). This study shows that KIR6.2 polymorphisms are frequently associated with Type II diabetes in French Caucasians. Furthermore, a meta-analysis combining different Caucasian groups suggests an significant role of KIR6.2 in the polygenic context of Type II diabetes.

Aged↗
PubMed1996

Heterogeneity of hypothalamic-pituitary-adrenal system response to a combined dexamethasone-CRH test in multiple sclerosis.

The endocrine system participates in the regulation of the immune and neural systems and therefore hormonal factors probably play an important role in the development and course of multiple sclerosis (MS). Specifically, the hypothalamic-pituitary-adrenal (HPA) system seems crucial because (a) the inflammatory response is accompanied by HPA activation; (b) animal models with an inherited HPA defect are prone to developing experimental autoimmune encephalitis; and (c) most important, corticosteroids are still the most widely used treatment. We administered a recently developed neuroendocrine function test that combines dexamethasone suppression (1.5 mg orally at 2300 h) and corticotropin-releasing hormone (CRH) stimulation (100 micrograms i.v. at 1500 h the following day) and measured the response of plasma cortisol and corticotrophin (ACTH) secretion in 19 patients with an acute exacerbation of MS. These patients had a significantly higher mean plasma cortisol response than age-matched controls (peak minus baseline; 48.1 +/- 10.5 ng/ml [mean +/- SEM] versus 19.8 +/- 4.2 ng/ml; p < 0.05), but the corresponding ACTH values for the two groups were indistinguishable (13.4 +/- 1.4 pg/ml [mean +/- SEM] versus 11.3 +/- 1.4 pg/ml; n.s.). The response range in the patients was broader and we identified six patients with excessive cortisol release (peak minus baseline: 100.5 +/- 14.4 ng/ml [mean +/- SEM]), whereas four patients failed to respond at all. The hormonal response patterns were not related to previous treatments with corticosteroids or other immunosuppressants or to psychopathological features. These results point to a heterogeneity of HPA system function, most likely at the corticosteroid receptor level, which has clinical implications for all those treatments that affect the HPA system and the course of MS.

Adrenocorticotropic Hormone↗
PubMed2006

Shrunken p-values for assessing differential expression with applications to genomic data analysis.

In many scientific problems involving high-throughput technology, inference must be made involving several hundreds or thousands of hypotheses. Recent attention has focused on how to address the multiple testing issue; much focus has been devoted toward the use of the false discovery rate. In this article, we consider an alternative estimation procedure titled shrunken p-values for assessing differential expression (SPADE). The estimators are motivated by risk considerations from decision theory and lead to a completely new method for adjustment in the multiple testing problem. In addition, the decision-theoretic framework can be used to derive a decision rule for controlling the number of false positive results. Some theoretical results are outlined. The proposed methodology is illustrated using simulation studies and with application to data from a prostate cancer gene expression profiling study.

Biometry↗
PubMed2005

Fecundity and pregnancy outcome in a cohort with sickle cell-haemoglobin C disease followed from birth.

OBJECTIVE: To compare pregnancy outcome in sickle cell-haemoglobin C (SC) disease with that in homozygous sickle cell (SS) disease and age-matched controls with a normal haemoglobin (AA) genotype. DESIGN: A cohort study followed from birth. SETTING: Sickle Cell Clinic, University Hospital and other Jamaican hospitals. POPULATION: Ninety-five pregnancies in 43 patients with SC disease, 94 pregnancies in 52 patients with SS disease and 157 pregnancies in 68 controls. METHODS: Systematic review of all pregnancies occurring in sample population. Kaplan-Meier analysis for interval to first pregnancy, and the t test, chi2 test or Fisher's exact test as appropriate; correction was made for multiple testing and multiple linear regression was used for analysis of determinants of birthweight. MAIN OUTCOME MEASURES: Age at menarche, interval to first pregnancy, outcome of pregnancy, maternal complications and possible predictors of low birthweight. RESULTS: Menarche was marginally delayed in SC disease compared with AA controls (median age 13.7 vs 13.0 years, P= 0.02) but age at first pregnancy was similar (median age 22.5 vs 20.1 years, P= 0.32). Pregnancy outcome in SC disease did not differ from AA controls but compared with SS disease there were marginally fewer miscarriages, more live deliveries and greater birthweight. The prevalence of pregnancy-induced hypertension, pre-eclampsia, antepartum or postpartum haemorrhage in SC disease did not differ from AA controls but the prevalence of sickle-related complications was similar to SS disease. CONCLUSIONS: Contrary to some claims, pregnancy outcome in SC disease is generally benign compared with SS disease.

Adolescent↗
PubMed2005

Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence.

We tested six single nucleotide polymorphisms (SNPs) in the alpha4 subunit gene (CHRNA4) and four SNPs in the beta2 subunit gene (CHRNB2) of nicotinic acetylcholine receptors (nAChRs) for association with nicotine dependence (ND), which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) in 2037 subjects from 602 nuclear families of either European-American (EA) or African-American (AA) ancestry. Analysis of the six SNPs within CHRNA4 demonstrated that in the EA sample SNPs rs2273504 and rs1044396 are significantly associated with the adjusted SQ and FTND score, respectively. In the AA samples, SNPs rs3787137 and rs2236196 are each significantly associated with at least two adjusted ND measures. Association of rs2236196 with the adjusted HSI and FTND scores in the AA samples remained significant after correction for multiple testing. Furthermore, analysis revealed gender- and ethnic-specific associations for several SNPs with ND measures in both ethnic samples; however, only the association of SNP rs2236196 with the three adjusted ND measures remained significant after correcting for multiple testing in the AA female samples. Haplotype analysis of rs2273505-rs2273504-rs2236196 showed significant association after Bonferroni correction of a C-G-G haplotype (53.4%) with three adjusted ND measures in samples from the AA females. A similar analysis for the four SNPs within CHRNB2 did not reveal significant association with the three ND measures. In summary, our findings provide convincing evidence for the involvement of the nAChR alpha4 subunit, but not of the nAChR beta2 subunit, in nicotine addiction.

Black People↗
PubMedDate not supplied

Genetic testing in multiple endocrine neoplasia and related syndromes.

Multiple Endocrine Neoplasia (MEN) syndromes are inherited diseases characterised by endocrine tumours occuring as autosomal dominant genetic diseases with high penetrance. In MEN1, most tumours affect the parathyroids, endocrine pancreas, anterior pituitary, and adrenal glands. The MEN1 gene has been cloned recently and encodes a nuclear protein without known function so far. More than 200 germline mutations have been identified in MEN1 patients throughout the entire coding sequence and no genotype-phenotype correlation has been found. Now, MEN1 gene screening is a powerful tool in pre-symptomatic diagnosis for MEN1 patients and those with inherited MEN1 related syndromes. MEN2 refers to the inherited forms of medullary thyroid carcinoma (MTC) which is associated with phaechromocytoma and parathyroid tumours in MEN2A, phaechromocytoma and mucosal neuromas in MEN2B. Familial isolated MTC is characterised by MTC only, and the three variants of MEN2 are related to germline missense mutations of the RET proto-oncogene, which encodes a tyrosine-kinase receptor. Germline RET mutations in MEN2 patients are related to the two main functionnal domains in the RET protein, the extracellular ligand binding domain (MEN2A and FMTC) and the intracellular catalytic domain (MEN2A, MEN2B and FMTC). Genotype-phenotype correlations have been established but must be used carefully in clinical practice. RET mutation analysis is now available for patients and prophylactic thyroidectomy in gene-carriers could be the most reliable way to cure the patients. Mechanisms of tumourigenesis induced by MEN2-related RET germline mutations have been analysed by in vitro studies and the generation of transgenic mice which develop true bilateral MTC. Recent insights on MEN syndrome pathogenesis and related inherited endocrine disorders have a major clinical impact and fundamental studies are now in progress in order to identify all genetic events leading from a normal endocrine tissue towards a fully malignant phenotype.

Adult↗
PubMed2000

Analysis of multivariate failure-time data from HIV clinical trials.

We illustrate the use of marginal methods for the analysis of multivariate failure-time data using a large trial in HIV infection in which the composite endpoint of AIDS or death incorporates more than 20 events with varying severity. Multivariate failure-time methods are required to investigate whether treatment delays development of new AIDS events. AIDS events can be grouped and treatment effects estimated using only the first event to occur in each group for each individual. Alternatively, all events can be included by fitting a separate baseline hazard for development of each event, and restricting treatment effects to be common within groups of events. In either case, model-based or minimum-variance estimates of the overall effect of treatment can be constructed. The covariance matrix for the treatment-effect estimates can be used in multiple testing procedures. Results from the Delta trial suggest that combination antiretroviral therapy with AZT plus either ddI or ddC may delay progression to more severe AIDS events compared to AZT monotherapy. These late events are generally untreatable and prophylaxis is not available. Trials are not generally powered to detect treatment effects on individual events making up a composite endpoint, and therefore all analyses are exploratory rather than providing definitive evidence. However, marginal multivariate models provide an easily available approach for modeling the effect of covariates on multiple disease processes, and allow the likely effects of treatment to be presented in a manner which is easily understood. They can be used in a variety of ways to explore different patterns of treatment effects and are also useful for testing multiple hypotheses regarding treatment effects on several different composite endpoints.

Acquired Immunodeficiency Syndrome↗