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PubMed2006

PDA: Pooled DNA analyzer.

BACKGROUND: Association mapping using abundant single nucleotide polymorphisms is a powerful tool for identifying disease susceptibility genes for complex traits and exploring possible genetic diversity. Genotyping large numbers of SNPs individually is performed routinely but is cost prohibitive for large-scale genetic studies. DNA pooling is a reliable and cost-saving alternative genotyping method. However, no software has been developed for complete pooled-DNA analyses, including data standardization, allele frequency estimation, and single/multipoint DNA pooling association tests. This motivated the development of the software, 'PDA' (Pooled DNA Analyzer), to analyze pooled DNA data. RESULTS: We develop the software, PDA, for the analysis of pooled-DNA data. PDA is originally implemented with the MATLAB language, but it can also be executed on a Windows system without installing the MATLAB. PDA provides estimates of the coefficient of preferential amplification and allele frequency. PDA considers an extended single-point association test, which can compare allele frequencies between two DNA pools constructed under different experimental conditions. Moreover, PDA also provides novel chromosome-wide multipoint association tests based on p-value combinations and a sliding-window concept. This new multipoint testing procedure overcomes a computational bottleneck of conventional haplotype-oriented multipoint methods in DNA pooling analyses and can handle data sets having a large pool size and/or large numbers of polymorphic markers. All of the PDA functions are illustrated in the four bona fide examples. CONCLUSION: PDA is simple to operate and does not require that users have a strong statistical background. The software is available at http://www.ibms.sinica.edu.tw/%7Ecsjfann/first%20flow/pda.htm.

Algorithms↗
PubMed2004

Characterization of common genetic variants in cathepsin K and testing for association with bone mineral density in a large cohort of perimenopausal women from Scotland.

UNLABELLED: BMD values in approximately 3000 perimenopausal Scottish women were adjusted by regression to identify and account for nongenetic factors. Adjusted BMD values were not associated with simple tandem repeat (STR) markers or single nucleotide polymorphisms (SNPs) at the Cathepsin K (CTSK) locus. We present a thorough analysis of common CTSK polymorphisms and genetic relatedness among CTSK haplotypes. INTRODUCTION: CTSK is a cysteine protease of the papain family and is thought to play a critical role in osteoclast-mediated bone degradation. Rare, inactivating mutations in CTSK cause pychodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature. However, there have been no studies of common genetic variants in CTSK and their possible association with bone density in the general population. MATERIALS AND METHODS: To identify common single nucleotide polymorphisms (SNPs) and simple tandem repeat (STR) polymorphisms in and around CTSK, we screened all CTSK exons, intron A, all intron-exon boundaries, and the putative CTSK promoter region in 130 random whites using both high-performance liquid chromatography (HPLC) and DNA sequencing. CTSK markers were genotyped in approximately 3000 perimenopausal Scottish women whose hip and spine bone mineral density (BMD) had been measured by DXA. We performed linear regression analysis to identify and adjust for nongenetic predictors of BMD, and adjusted BMD values (regression residuals) were tested for association with individual CTSK markers and haplotypes by ANOVA and the composite haplotype method of Zaykin et al. RESULTS AND CONCLUSIONS: We discovered two intronic SNPs (8% and 9% frequency), but no common exonic SNPs (> 1% frequency), and found that three STRs at the immediate 5' end of the CTSK locus are highly polymorphic. The population frequencies of haplotypes defined by these five polymorphisms were estimated, and a cladogram was derived showing proximity of relationship and likely descent of the 30 most common CTSK haplotypes. Regression analyses revealed that approximately 39% of spine and 19% of hip rate of change in BMD was accounted for by nongenetic factors. For baseline BMD values in premenopausal women, nongenetic predictors explained 11% of the variance at the spine and 13% at the hip. Adjusted BMD values showed no statistically significant association with any of the individual CTSK polymorphisms or CTSK haplotypes.

Analysis of Variance↗
PubMed1999

Assessment of executive function in patients with mild traumatic brain injury.

BACKGROUND: The nature of functional deficit after mild traumatic brain injury (TBI) defined by Glasgow Coma Score of 13-15 is not fully described. This study explored the sensitivity of several neuropsychological tests to identify sequelae of mild traumatic brain injury (TBI). METHODS: Eleven adult patients with mild TBI admitted to a Level 1 trauma center were studied. The battery of tests included the Wechsler Intelligence Scale for Children -Revised: Mazes Subtest, Trails A and B, the Boston Naming Test, The Multilingual Aphasia Examination: Controlled Oral Word Association Test, and the Paced Auditory Serial Addition Task. RESULTS: Control subjects performed significantly better than patients with mild TBI on Trails A and B, the Controlled Oral Word Association Test, and Paced Auditory Serial Addition Task (subtests 2-4). No significant differences in performances between patients and controls was found for the Wechsler Intelligence Scale for Children -Revised: Mazes Subtest, Boston Naming Test, and Paced Auditory Serial Addition Task Subtest 1. CONCLUSION: The results suggest that tests of specific frontal lobe executive functions are valuable in diagnosing and monitoring recovery from mild TBI.

Adult↗
PubMed2001

UMPU and alternative tests for association in 2 x 2 tables.

The use of the uniformly most powerful among the unbiased (UMPU) test was recently suggested for the study of gametic association between two polymorphic loci as an alternative to the Fisher's exact test (Zapata and Alvarez, 1997, Annals of Human Genetics 61, 71-77). However, the proposed test is not UMPU for two-sided alternatives. In this study, we present the UMPU test, discuss criticisms against the use of randomized tests, and compare the power of several tests. We show that, in many practical cases, the use of the UMPU test is less than desirable and propose the alternative adjusted-more extreme tables (A-MET) and the equal-tails (ET) tests. We suggest that some of the general arguments against the use of randomized tests can be alleviated by a newly proposed extended p-value definition.

Bias↗
PubMed2005

Identification of polymorphisms explaining a linkage signal: application to the GAW14 simulated data.

We applied three approaches for the identification of polymorphisms explaining the linkage evidence to the Genetic Analysis Workshop 14 simulated data: 1) the genotype-IBD sharing test (GIST); 2) an approach suggested by Horikawa and colleagues; and 3) the homozygote sharing test (HST). These tests were compared with a family-based association test. Two linked regions with highest nonparametric linkage scores were selected to apply these methods. In the first region, Horikawa's method identified the most SNPs within the region containing the disease susceptibility locus, while HST performed best in the second region. However, Horikawa's method also had the most type I errors. These methods show potential as additional tools to complement family-based association tests for the identification of disease susceptibility variants.

Chromosomes, Human, Pair 1↗
PubMed1998

Using information from both parents when testing for association between marker and disease loci.

Several extensions of the transmission/disequilibrium test (TDT) to multi-allelic markers now exist. In some of these, however, separate tests must be performed on male and female parents because of the non-independence of parental transmission patterns, reducing power, and complicating interpretation of the test results. Here we show that this non-independence is asymptotically irrelevant when using the allelic TDT of Bickeböller and Clerget-Darpoux [(1995) Genet Epidemiol 12:577-582], allowing the analysis of data from both parents simultaneously.

Alleles↗
PubMed1992

[Word association and schizophrenia--an empirical study].

Since Bleuler's (1911) work on dementia praecox, numerous studies on associative disturbances in schizophrenics have been published. Methodological flaws and difficulties in interpreting the disturbances consistently have brought about a certain dilemma: they are unanimously considered a basic disorder in schizophrenia, but the problem of their reliable evaluation has remained unanswered. 43 schizophrenics, 15 affective psychotics, and 46 normals were investigated in order to compare different forms of the word association test (WAT). The schizophrenics gave less common responses than the normals in the free association task. However, the two groups differed more widely in their performance when asked to respond "individually", "commonly", or using a multiple-choice associative test. The affective psychotics were similar in their response behaviour, partly to the schizophrenics (free and common response conditions; multiple-choice test), partly to the normals (individual response condition). The relationship of the WAT to personality characteristics (Eysenck's psychoticism), the influence of psychopathology and the course of the disease, the patients' well-being and self-report of speech and thought disorders are discussed.

Acute Disease↗
PubMed2005

Power and related statistical properties of conditional likelihood score tests for association studies in nuclear families with parental genotypes.

Both population based and family based case control studies are used to test whether particular genotypes are associated with disease. While population based studies have more power, cryptic population stratification can produce false-positive results. Family-based methods have been introduced to control for this problem. This paper presents the full likelihood function for family-based association studies for nuclear families ascertained on the basis of their number of affected and unaffected children. The likelihood of a family factors into the probability of parental mating type, conditional on offspring phenotypes, times the probability of offspring genotypes given their phenotypes and the parental mating type. The first factor can be influenced by population stratification, whereas the latter factor, called the conditional likelihood, is not. The conditional likelihood is used to obtain score tests with proper size in the presence of population stratification (see also Clayton (1999) and Whittemore & Tu (2000)). Under either the additive or multiplicative model, the TDT is known to be the optimal score test when the family has only one affected child. Thus, the class of score tests explored can be considered as a general family of TDT-like procedures. The relative informativeness of the various mating types is assessed using the Fisher information, which depends on the number of affected and unaffected offspring and the penetrances. When the additive model is true, families with parental mating type Aa x Aa are most informative. Under the dominant (recessive) model, however, a family with mating type Aa x aa(AA x Aa) is more informative than a family with doubly heterozygous (Aa x Aa) parents. Because we derive explicit formulae for all components of the likelihood, we are able to present tables giving required sample sizes for dominant, additive and recessive inheritance models.

Case-Control Studies↗
PubMed1979

Cellular tumorigenicity in nude mice. Test of associations among loss of cell-surface fibronectin, anchorage independence, and tumor-forming ability.

Fibronectin (FN; also called large external transformation-sensitive [LETS] protein or cell-surface protein [CSP]) is a large cell-surface glycoprotein that is frequently observed to be either absent or greatly reduced on the surfaces of malignant cells grown in vitro. Because FN may be a useful molecular marker of cellular malignancy, we have carried out an extensive screening to test the specific association among the degree of expression of FN, anchorage-independent growth, and tumorigenicity in the athymic nude mouse. A variety of diploid cell strains and established cell lines were tested for the expression of surface FN by indirect immunofluorescence using rabbit antisera against human cold insoluble globulin, rodent plasma FN, or chicken cell-surface FN. Concomitantly, the cells were assayed for tumor formation in nude mice and for the ability to form colonies in methylcellulose. Tumorigenic cells often showed very low surface fluorescence, confirming earlier reports. However, many highly tumorigenic fibroblast lines from several species stained strongly with all three antisera. In contrast, the anchorage-independent phenotype was nearly always associated with tumorigenicity in approximately 35 cell lines examined in this study. In another series of experiments, FN-positive but anchorage-independent cells were grown as tumors in nude mice and then reintroduced into culture. In five of the six tumor-derived cell lines, cell-surface FN was not significantly reduced; one such cell line showed very little surface FN. Our data thus indicate that the loss of cell-surface FN is not a necessary step in the process of malignant transformation and that the growth of FN-positive cells as tumors does not require a prior selection in vivo for FN-negative subpopulations.

Animals↗
PubMed1985

Tests of association of lymphocyte alloantigen genotypes with resistance to viral oncogenesis in chickens. 2. Rous sarcoma and lymphoid leukosis in progeny derived from 6(3) X 15(1) and 100 X 6(3) crosses.

Chickens from inbred line RPRL 6(3) are resistant to virally-induced Marek's disease (MD) and lymphoid leukosis (LL) and are relatively strong regressors of virally induced Rous sarcomas. Line 6(3) chickens are homozygous for three independent loci determining surface alloantigens of lymphocytes, Th-1 and Ly-4 on thymus-derived (T) cells and Bu-1 on bursa-derived (B) cells. In contrast, RPRL Lines 100 and 15(1) are highly susceptible to MD and LL and are weaker regressors of Rous sarcomas than 6(3). RPRL Lines 100 and 15(1) are homozygous for different alleles at the Th-1 and Ly-4 loci than 6(3), whereas only Line 100 differs from 6(3) at Bu-1. To test the possible association of these three antigen loci with variations in resistance to virally-induced tumors, homozygous genotypes among later generations derived from 6(3) X 15(1) and 100 X 6(3) crosses were identified by means of immunofluorescence testing of peripheral blood lymphocytes. Test progeny were then bred from matings of homozygous parents. No association was found between Rous sarcoma regression and the Th-1 and Ly-4 T cell alloantigen loci in F6 (6(3) X 15(1)) chickens, but the Bu-1 locus influenced rate of regression in F3 (100 X 6(3)) chickens. The Ly-4 in F6 (6(3) X 15(1)) and Bu-1 in the F3 (100 X 6(3)) chickens did not influence the incidence of LL. However, Th-1 influenced LL in F3 (100 X 6(3)) chickens (P less than .05) and possibly influenced LL in F6 (6(3) X 15(1)) chickens (P less than .09).

Animals↗
PubMed2003

Methane production during lactulose breath test is associated with gastrointestinal disease presentation.

It has recently been determined that there is an increased prevalence of bacterial overgrowth in IBS. Since there are two gases (hydrogen and methane) measured on lactulose breath testing, we evaluated whether the different gas patterns on lactulose breath testing coincide with diarrhea and constipation symptoms in IBS and IBD. Consecutive patients referred to the gastrointestinal motility program at Cedars-Sinai Medical Center for lactulose breath testing were given a questionnaire to evaluate their gastrointestinal symptoms. Symptoms were graded on a scale of 0-5. Upon completion of the breath test, the results were divided into normal, hydrogen only, hydrogen and methane, and methane only positive breath tests. A comparison of all subjects and IBS subjects was undertaken to evaluate diarrhea and constipation with regards to the presence or absence of methane. This was further contrasted to Crohn's and ulcerative colitis (UC) patients in the database. After exclusion criteria, 551 subjects from the database were available for comparison. Of the 551 subjects (P < 0.05, one-way ANOVA) and in a subgroup of 296 IBS subjects (P < 0.05, one-way ANOVA), there was a significant association between the severity of reported constipation and the presence of methane. The opposite was true for diarrhea (P < 0.001). If a breath test was methane positive, this was 100% associated with constipation predominant IBS. Furthermore, IBS had a greater prevalence of methane production than Crohn's or UC. In fact, methane was almost nonexistent in the predominantly diarrheal conditions of Crohn's and UC. In conclusion, a methane positive breath test is associated with constipation as a symptom.

Breath Tests↗
PubMed1992

[The adenosine test in association with 99m-technetium sestamibi tomoscintigraphy in the diagnosis of coronary pathology].

BACKGROUND: The exogenous adenosine is able to provoke a coronary vasodilation, which is the same as the one provoked by the papaverine and greater than the one provoked by the dipyridamole. We report our experience in using exogenous adenosine in association with technetium-99m-sestamibi tomoscintigraphy for a diagnostic test on the coronary artery disease (CAD). METHODS: We considered 22 patients (18 male and 4 female, mean age 57 years) affected by angiographically demonstrated coronary artery disease (stenoses > or = 50%). Adenosine was infused at a dosage of 0.070 mg/kg/min for 3 minutes and, if well tolerated, the dosage was increased to 0.140 mg/kg/min; in the third minute of the major dosage the radioisotope was injected. The myocardial perfusion imaging at rest was evaluated on the following day. RESULTS: The test was completed on 21 of the 22 patients, and 20 of the latter were subjected to the maximal dosage of the adenosine infusion. Clinically irrelevant adverse effects were observed in 20 cases; only one patient developed a II degree type 1 AV block. Angina occurred in 19 patients. Coronary angiography demonstrated significant stenosis of 35 vessels: the left anterior descending (LAD) in 14 patients, the left circumflex (LCx) in 8 and the right coronary artery (RCA) in 13. In detecting CAD, the test in our study demonstrated a sensitivity of 85% in the LAD disease, of 89% in the LCx disease and of 77% in RCA disease. CONCLUSIONS: The adenosine infusion associated with technetium-99m-sestamibi tomoscintigraphy demonstrated an elevated incidence of adverse effects which are of short duration and clinically irrelevant. The method was shown to be highly sensitive in detecting the CAD.

Adenosine↗
PubMed1991

Incubation and the persistence of fixation in problem solving.

Extra work on unsolved problems may lead to more improvement if the new work is delayed rather than undertaken immediately after initial solution attempts. Such a result constitutes incubation in problem solving. "Unconscious work" on a problem, commonly assumed to be responsible for incubation effects, may not be necessary to observe the phenomenon. We hypothesize that fixation, a block to successful problem solving, may develop during initial solution attempts and persist, interfering with immediate extra work more than with delayed extra work. Five experiments are reported in which fixation was induced to prevent optimal performance on the initial test of Remote Associates Test (RAT) problems (e.g., Mednick, 1962). After the fixation manipulation in three of the experiments, the effects of incubation intervals were examined by retesting the fixated problems. Both fixation (poorer initial problem-solving performance) and incubation (more improvement after a delayed retest than an immediate retest) were found in all the experiments which tested for the effects. In Experiments 1, 2, and 3, misleading distractors were presented alongside the RAT problems during the initial test of the problems to cause fixation. In Experiment 4, a block of paired associates--pairing the RAT words with the misleading distractors prior to problem solving--successfully induced fixation, indicating that the distractors affected memory retrieval. In Experiment 5, a trial-by-trial technique allowed fixation and incubation to be induced and tested separately for each item. All of our findings of incubation effects appear to have depended upon the initial induction of fixation. Although the experiments may not be representative of all naturally occurring cases of incubation, they provide a methodology for the study of fixation and incubation effects in problem solving in the laboratory.

Adult↗
PubMed1997

Relationships between verbal and nonverbal fluency measures: implications for assessment of executive functioning.

This experiment evaluated the relationship between verbal and nonverbal fluency measures commonly employed in neuropsychological assessment. Three fluency measures, the Controlled Oral Word Association Test, the Design Fluency Test, and the Ruff Figural Fluency Test, were administered to a sample of 61 men and 73 women in college. Analyses indicated that scores on the Controlled Oral Word Association Test were significantly correlated with scores on the Fixed but not the Free Condition of the Design Fluency Test. Scores on the Ruff test were significantly more closely correlated with the Fixed versus the Free Condition, although they were also correlated with the total scores on the Design Fluency Test. Differential correlations are discussed in terms of the varying structure inherent in the measures of fluency and their presumed taxing of frontally mediated executive processes.

Adolescent↗
PubMed2003

Pedigree disequilibrium tests for multilocus haplotypes.

Association tests of multilocus haplotypes are of interest both in linkage disequilibrium mapping and in candidate gene studies. For case-parent trios, I discuss the extension of existing multilocus methods to include ambiguous haplotypes in tests of models which distinguish between the cis and trans phase. A likelihood-ratio test is proposed, using the expectation-maximization (E-M) algorithm to account for haplotype ambiguities. Assumptions about the population structure are required, but realistic situations, including population stratification, which violate the assumptions lead to conservative tests. I describe a permutation procedure for the null hypothesis of interest, which controls for violation of the assumptions. For general pedigrees, I describe extensions of the pedigree disequilibrium test to include uncertain haplotypes. The summary statistics are replaced by their expected values over prior distributions of haplotype frequencies. If prior distributions are not available, a valid test is possible by using the E-M algorithm to estimate the null distribution of haplotype frequencies. Similar methods are available for quantitative traits. Exact permutation tests are difficult to construct in small samples, but an approximate procedure is appropriate in large samples, and can be used to account for dependencies between tests of multiple haplotypes and loci.

Algorithms↗
PubMed2005

Whole-genome association studies of alcoholism with loci linked to schizophrenia susceptibility.

BACKGROUND: Alcoholism is a complex disease. There have been many reports on significant comorbidity between alcoholism and schizophrenia. For the genetic study of complex diseases, association analysis has been recommended because of its higher power than that of the linkage analysis for detecting genes with modest effects on disease. RESULTS: To identify alcoholism susceptibility loci, we performed genome-wide single-nucleotide polymorphisms (SNP) association tests, which yielded 489 significant SNPs at the 1% significance level. The association tests showed that tsc0593964 (P-value 0.000013) on chromosome 7 was most significantly associated with alcoholism. From 489 SNPs, 74 genes were identified. Among these genes, GABRA1 is a member of the same gene family with GABRA2 that was recently reported as alcoholism susceptibility gene. CONCLUSION: By comparing 74 genes to the published results of various linkage studies of schizophrenia, we identified 13 alcoholism associated genes that were located in the regions reported to be linked to schizophrenia. These 13 identified genes can be important candidate genes to study the genetic mechanism of co-occurrence of both diseases.

Alcoholism↗
PubMed1994

What association analysis can and cannot tell us about the genetics of complex disease.

Human genetics researchers have been intrigued for many years by weak-to-moderate associations between markers and diseases. However, in most cases of association, the cause of this phenomenon is still unknown. Recently, interest has grown in pursuing association studies for complex psychiatric diseases, either instead of or in addition to linkage studies. However, it is one thing to detect association; the next important step is to determine why. Here we consider what a disease-marker association in the weak-to-moderate range (relative risk < 5) can tell us about disease etiology. Two distinct models (not the only possibilities) which could explain such an association are formulated. One is a linkage disequilibrium or major disease gene model, involving tight linkage with a "necessary" major gene. The other is a pure association model, involving a "susceptibility" gene that has only a minor effect on disease state. It will be shown that association analysis cannot distinguish between these two models, and hence cannot elucidate the biological mechanism behind the association. (This statement holds for traditional population-based association tests, as well as for more recent family-based association tests.) The importance of drawing the distinction between these two genetic models and the implications for understanding the genetics of complex human disease will also be discussed.

Alcoholism↗