Biomedical subjects

Nancy R Mendell

Publications and source records attributed to Nancy R Mendell.

13 recordsLinked to original sources

PubMed2005

A gene-model-free method for linkage analysis of a disease-related-trait based on analysis of proband/sibling pairs.

In this paper we investigate the power of finding linkage to a disease locus through analysis of the disease-related traits. We propose two family-based gene-model-free linkage statistics. Both involve considering the distribution of the number of alleles identical by descent with the proband and comparing siblings with the disease-related trait to those without the disease-related-trait. The objective is to find linkages to disease-related traits that are pleiotropic for both the disease and the disease-related-traits. The power of these statistics is investigated for Kofendrerd Personality Disorder-related traits a (Joining/founding cults) and trait b (Fear/discomfort with strangers) of the simulated data. The answers were known prior to the execution of the reported analyses. We find that both tests have very high power when applied to the samples created by combining the data of the three cities for which we have nuclear family data.

Chromosome Mapping↗

PubMed2005

Using mixture models to characterize disease-related traits.

We consider 12 event-related potentials and one electroencephalogram measure as disease-related traits to compare alcohol-dependent individuals (cases) to unaffected individuals (controls). We use two approaches: 1) two-way analysis of variance (with sex and alcohol dependency as the factors), and 2) likelihood ratio tests comparing sex adjusted values of cases to controls assuming that within each group the trait has a 2 (or 3) component normal mixture distribution. In the second approach, we test the null hypothesis that the parameters of the mixtures are equal for the cases and controls. Based on the two-way analysis of variance, we find 1) males have significantly (p < 0.05) lower mean response values than females for 7 of these traits. 2) Alcohol-dependent cases have significantly lower mean response than controls for 3 traits. The mixture analysis of sex-adjusted values of 1 of these traits, the event-related potential obtained at the parietal midline channel (ttth4), found the appearance of a 3-component normal mixture in cases and controls. The mixtures differed in that the cases had significantly lower mean values than controls and significantly different mixing proportions in 2 of the 3 components. Implications of this study are: 1) Sex needs to be taken into account when studying risk factors for alcohol dependency to prevent finding a spurious association between alcohol dependency and the risk factor. 2) Mixture analysis indicates that for the event-related potential "ttth4", the difference observed reflects strong evidence of heterogeneity of response in both the cases and controls.

Alcoholism↗

PubMed2005

Summary of contributions to GAW Group 12: multivariate methods.

Here we summarize the contributions to Group 12 of Genetic Analysis Workshop (GAW) 14, held in Noordwijkerhout, The Netherlands. The theme of this group, multivariate methods, covered a broad range of statistical applications. Most of the contributors considered Problem 1 of the GAW. However, one paper considered the bivariate analysis of two binary phenotypes generated by the simulated data in Problem 2. Some contributors focused on statistical issues involved in considering multiple variables, and others on extensions to the variance-components methodology for analysis of quantitative traits. Applications to the Collaborative Study on the Genetics of Alcoholism data identified a single-nucleotide polymorphism (SNP) on chromosome 4 associated with the ttth1-ttth4 phenotypes, and replicated previous findings of linkage on chromosome 4 for alcohol consumption, using microsatellite and SNP data.

Alcoholism↗

PubMed2005

Intensive lifestyle changes may affect the progression of prostate cancer.

PURPOSE: Men with prostate cancer are often advised to make changes in diet and lifestyle, although the impact of these changes has not been well documented. Therefore, we evaluated the effects of comprehensive lifestyle changes on prostate specific antigen (PSA), treatment trends and serum stimulated LNCaP cell growth in men with early, biopsy proven prostate cancer after 1 year. MATERIALS AND METHODS: Patient recruitment was limited to men who had chosen not to undergo any conventional treatment, which provided an unusual opportunity to have a nonintervention randomized control group to avoid the confounding effects of interventions such as radiation, surgery or androgen deprivation therapy. A total of 93 volunteers with serum PSA 4 to 10 ng/ml and cancer Gleason scores less than 7 were randomly assigned to an experimental group that was asked to make comprehensive lifestyle changes or to a usual care control group. RESULTS: None of the experimental group patients but 6 control patients underwent conventional treatment due to an increase in PSA and/or progression of disease on magnetic resonance imaging. PSA decreased 4% in the experimental group but increased 6% in the control group (p = 0.016). The growth of LNCaP prostate cancer cells (American Type Culture Collection, Manassas, Virginia) was inhibited almost 8 times more by serum from the experimental than from the control group (70% vs 9%, p <0.001). Changes in serum PSA and also in LNCaP cell growth were significantly associated with the degree of change in diet and lifestyle. CONCLUSIONS: Intensive lifestyle changes may affect the progression of early, low grade prostate cancer in men. Further studies and longer term followup are warranted.

Aged↗

PubMed2004

Antisaccade performance in biological relatives of schizophrenia patients: a meta-analysis.

Poor performance on the antisaccade (AS) task has been interpreted as a potential indicator of genetic liability that may enhance the power of linkage studies of a multidimensional phenotype for schizophrenia. Every study has replicated the finding of significantly worse performance in schizophrenia patients regardless of which specific antisaccade paradigm was employed. In some studies involving a standard version of the antisaccade task, relatives of schizophrenia patients made an increased number of errors, but in other studies that used this same paradigm, relatives of schizophrenia patients did not differ from controls. In this paper, we report the results of a meta-analysis on studies that used the standard antisaccade paradigm. The meta-analysis shows that those studies that reported large effect sizes and statistically significant differences between relatives of schizophrenia patients and controls used inclusion/exclusion criteria that were not symmetrical between the two groups, whereas those studies that reported small and nonsignificant differences between relatives of schizophrenia patients and controls used symmetrical inclusion/exclusion criteria. Specifically, studies that applied stricter psychopathology exclusion criteria to controls than to relatives of schizophrenia patients had larger effect sizes than studies that applied comparable exclusion criteria to both groups, suggesting that antisaccade performance is compromised by psychopathology in general rather than by schizophrenia per se. Since symmetrical inclusion/exclusion criteria between relatives of schizophrenia patients and controls are essential for a genetic analysis, and those studies that did apply symmetrical criteria had small effect sizes, the available data suggest that poor antisaccade performance is unlikely to be useful in identifying clinically unaffected carriers of genes for schizophrenia.

Genotype↗

PubMed2004

Increasing power for tests of genetic association in the presence of phenotype and/or genotype error by use of double-sampling.

Phenotype and/or genotype misclassification can: significantly increase type II error probabilities for genetic case/control association, causing decrease in statistical power; and produce inaccurate estimates of population frequency parameters. We present a method, the likelihood ratio test allowing for errors (LRTae) that incorporates double-sample information for phenotypes and/or genotypes on a sub-sample of cases/controls. Population frequency parameters and misclassification probabilities are determined using a double-sample procedure as implemented in the Expectation-Maximization (EM) method. We perform null simulations assuming a SNP marker or a 4-allele (multi-allele) marker locus. To compare our method with the standard method that makes no adjustment for errors (LRTstd), we perform power simulations using a 2/k factorial design with high and low settings of: case/control samples, phenotype/genotype costs, double-sampled phenotypes/genotypes costs, phenotype/genotype error, and proportions of double-sampled individuals. All power simulations are performed fixing equal costs for the LRTstd and LRTae methods. We also consider case/control ApoE genotype data for an actual Alzheimer's study. The LRTae method maintains correct type I error proportions for all null simulations and all significance level thresholds (10%, 5%, 1%). LRTae average estimates of population frequencies and misclassification probabilities are equal to the true values, with variances of 10e-7 to 10e-8. For power simulations, the median power difference LRTae-LRTstd at the 5% significance level is 0.06 for multi-allele data and 0.01 for SNP data. For the ApoE data example, the LRTae and LRTstd p-values are 5.8 x 10e-5 and 1.6 x 10e-3, respectively. The increase in significance is due to adjustment in the LRTae for misclassification of the most commonly reported risk allele. We have developed freely available software that performs our LRTae statistic.

Journal Article↗

PubMed2004

Human leukocyte antigen class II alleles influence levels of antibodies to the Plasmodium falciparum asexual-stage apical membrane antigen 1 but not to merozoite surface antigen 2 and merozoite surface protein 1.

The apical membrane antigen 1 (AMA1), merozoite surface antigen 2 (MSA2), and merozoite surface protein 1 (MSP1) are asexual-stage proteins currently being evaluated for inclusion in a vaccine for Plasmodium falciparum. Accordingly, it is important to understand factors that control antibody responses to these antigens. Antibody levels in plasma from residents of Etoa, Cameroon, between the ages of 5 and 70 years, were determined using recombinant AMA1, MSA2, and the N-terminal region of MSP1 (MSP1-190L). In addition, antibody responses to four variants of the C-terminal region of MSP1 (MSP1(19)) were assessed. Results showed that all individuals produced antibodies to AMA1, MSA2, and MSP1-190L; however, a proportion of individuals never produced antibodies to the MSP1(19) variants, although the percentage of nonresponders decreased with age. The influence of age and human leukocyte antigen (HLA)-DRB1/DQB1 alleles on antibody levels was evaluated using two-way analysis of variance. Age was correlated with levels of antibodies to AMA1 and MSP1(19) but not with levels of antibodies to MSA2 and MSP1-190L. No association was found between a single HLA allele and levels of antibodies to MSA2, MSP1-190L, or any of the MSP1(19) variants. However, individuals positive for DRB1*1201 had higher levels of antibodies to the variant of recombinant AMA1 tested than did individuals of all other HLA types. Since the effect was seen across all age groups, HLA influenced the level but not the rate of antibody acquisition. This association for AMA1, combined with the previously reported association between HLA class II alleles and levels of antibodies to rhoptry-associated protein 1 (RAP1) and RAP2, indicates that HLA influences the levels of antibodies to three of the five vaccine candidate antigens that we have evaluated.

Adolescent↗

PubMed2004

Percentiles of the null distribution of 2 maximum lod score tests.

We here consider the null distribution of the maximum lod score (LOD-M) obtained upon maximizing over transmission model parameters (penetrance values, dominance, and allele frequency) as well as the recombination fraction. Also considered is the lod score maximized over a fixed choice of genetic model parameters and recombination-fraction values set prior to the analysis (MMLS) as proposed by Hodge et al. The objective is to fit parametric distributions to MMLS and LOD-M. Our results are based on 3,600 simulations of samples of n = 100 nuclear families ascertained for having one affected member and at least one other sibling available for linkage analysis. Each null distribution is approximately a mixture p(2)(0) + (1 - p)(2)(v). The values of MMLS appear to fit the mixture 0.20(2)(0) + 0.80chi(2)(1.6). The mixture distribution 0.13(2)(0) + 0.87chi(2)(2.8). appears to describe the null distribution of LOD-M. From these results we derive a simple method for obtaining critical values of LOD-M and MMLS.

Alleles↗

PubMed2004

The antisaccade task and neuropsychological tests of prefrontal cortical integrity in schizophrenia: empirical findings and interpretative considerations.

To date, every published study of the antisaccade task has replicated the finding that schizophrenia patients make an increased number of errors. This finding has been interpreted as support for frontal and/or basal ganglia dysfunction in schizophrenia, primarily because neurological patients with pathology in these brain regions also make large numbers of errors on the antisaccade task. Here, we compared the performance of schizophrenia patients and nonpsychiatric controls on an antisaccade task and on two neuropsychological tests, the Wisconsin Card Sorting Test, which is assumed to tap frontal lobe functioning, and the interference condition of the Stroop Test, which is thought to tap dorsolateral prefrontal cortex/anterior cingulate functioning. We examined the pattern of intercorrelations among these tasks. Schizophrenia patients made significantly more errors on the antisaccade task, made more perseverative errors and achieved fewer categories on the Wisconsin Card Sorting Test, and were significantly slower during the interference condition of the Stroop Test than were nonpsychiatric controls. Antisaccade errors were significantly correlated with interference performance on the Stroop in schizophrenia patients and in controls, but were not significantly correlated with the measures of Wisconsin Card Sorting Test performance in either group. The pattern of intercorrelation suggests that these tasks should not be thought of as representing a unitary variable of "frontal cortical integrity". Although aspects of these tasks tap the ability to inhibit prepotent responses, each task is also behaviorally complex. The multifaceted nature of these tasks makes it difficult to isolate which brain regions are part of the network underlying the specific act of inhibiting a prepotent response (for example, the reflexive saccade toward the novel peripheral target) and which regions participate in aspects of task performance that are related to non-inhibitory components (for example, executing an antisaccade). A broadly distributed network is undoubtedly involved in both processes. Parsing the various components of cognitively complex tasks may help to clarify both the specific behaviors that are anomalous and their underlying neural substrates. We also address the complexity of inferring localized brain dysfunction in schizophrenia patients based on seemingly analogous behavioral deficits in neurological populations.

Journal Article↗

PubMed2003

Power of maximum HLOD tests to detect linkage to obesity genes.

BACKGROUND: We investigate the power of heterogeneity LOD test to detect linkage when a trait is determined by several major genes using Genetic Analysis Workshop 13 simulated data. We consider three traits, two of which are disease-causing traits: 1) the rate of change in body mass index (BMI); and 2) the maximum BMI; and 3) the disease itself (hypertension). Of interest is the power of "HLOD2", the maximum heterogeneity LOD obtained upon maximizing over the two genetic models. RESULTS: Using a trait phenotype Obesity Slope, we observe that the power to detect the two markers closest to the two genes (S1, S2) at the 0.05 level using HLOD2 is 13% and 10%. The power of HLOD2 for Max BMI phenotype is 12% and 9%. The corresponding values for the Hypertension phenotype are 8% and 6%. CONCLUSION: The power to detect linkage to the slope genes is quite low. But the power using disease-related traits as a phenotype is greater than the power using the disease (hypertension) phenotype.

Adult Children↗

PubMed2003

Locating disease genes using Bayesian variable selection with the Haseman-Elston method.

BACKGROUND: We applied stochastic search variable selection (SSVS), a Bayesian model selection method, to the simulated data of Genetic Analysis Workshop 13. We used SSVS with the revisited Haseman-Elston method to find the markers linked to the loci determining change in cholesterol over time. To study gene-gene interaction (epistasis) and gene-environment interaction, we adopted prior structures, which incorporate the relationship among the predictors. This allows SSVS to search in the model space more efficiently and avoid the less likely models. RESULTS: In applying SSVS, instead of looking at the posterior distribution of each of the candidate models, which is sensitive to the setting of the prior, we ranked the candidate variables (markers) according to their marginal posterior probability, which was shown to be more robust to the prior. Compared with traditional methods that consider one marker at a time, our method considers all markers simultaneously and obtains more favorable results. CONCLUSIONS: We showed that SSVS is a powerful method for identifying linked markers using the Haseman-Elston method, even for weak effects. SSVS is very effective because it does a smart search over the entire model space.

Bayes Theorem↗

PubMed2003

Antisaccade performance is abnormal in schizophrenia patients but not in their biological relatives.

Numerous studies have replicated the finding that schizophrenia patients make an increased number of errors on an antisaccade task. Some studies have reported that relatives of schizophrenia patients also make an increased number of antisaccade errors, a finding that has been interpreted to support the usefulness of compromised antisaccade performance as an index of genetic liability for schizophrenia. We examined performance on an antisaccade task in schizophrenia patients, nonpsychiatric controls, first-degree relatives of schizophrenia patients and first-degree relatives of nonpsychiatric controls. Schizophrenia patients made significantly more errors than did nonpsychiatric controls, but relatives of schizophrenia patients did not differ from relatives of controls or from all controls. Increased antisaccade errors on the standard version of the antisaccade task are associated with schizophrenia, but do not seem to be a co-familial trait for schizophrenia.

Adult↗

PubMed2003

A method for evaluating the results of Bayesian model selection: application to linkage analyses of attributes determined by two or more genes.

OBJECTIVES: We apply and evaluate the intrinsic Bayes factor (IBF) of Berger and Pericchi [J Am Stat Assoc 1996;91:109-122; Bayesian Statistics, Oxford University Press, vol 5, 1996] to linkage analyses done using the stochastic search variable selection (SSVS) method of George and McCulloch [J Am Stat Assoc 1993;88:881-889] as proposed by Suh et al. [Genet Epidemiol 2001;21(suppl 1):S706-S711]. METHODS: We consider 20 simulations of linkage data obtained under two different generating models. The SSVS is applied to a multiple regression extension [Genet Epidemiol 2001;21(suppl 1): S706-S711] of the Haseman-Elston [Behav Genet 1972;2:3-19; Genet Epidemiol 2000;19:1-17] methods. Four prior distributions are considered. We apply the IBF criterion to those samples where different prior distributions result in different top models. RESULTS: In those samples where three different models were obtained using the four priors, application of the IBFs eliminated one of the two wrong models in 4 out of 5 situations. Further elimination using the IBF criterion for situations with two different subsets did not serve as well. CONCLUSIONS: When different priors result in three or more different subsets of markers, one can use the IBF to get this number down to two for consideration. When two subsets result we recommend that both be considered.

Bayes Theorem↗