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Family-based tests of association in the presence and absence of known linkage.

Correlation among sibling marker genotypes may invalidate the results of family-based tests of association in the presence of linkage. We apply an empirical variance estimation method, which is implemented in the program package FBAT, on Caucasian families with asthma in the presence and absence of linkage and compare the results with those obtained using the TDT (TDTEX-PAIRS) on the same data sets. Our results indicate that both tests generally perform comparably in either setting.

Adult↗

The Word Association Implications Test.

Three experiments (N = 144 college students) tested and documented the relationship between incidental learning of diagnostic schemata with performance on the Word Association Implications Test (WAIT). Moreover, Experiment 1 showed that instruction in diagnostic cues did not improve WAIT scores, although an incentive did. Experiment 2 supported the "developing schemata" concept by showing that subjects need to interpret WAIT protocols before they can generate possible diagnostic clues. Experiment 3 showed that inductive reasoning and viewing the task as more play- and game-like (vs. work- and test-like) predicted WAIT scores over and above the influence of incidental learning of schemata, in sum, results suggest that an heuristic discovery-oriented approach is most successful in learning "to read between the lines" of word associations. Discussion addresses the value of heuristic versus algorithmic approaches to the learning of personality assessment.

Journal Article↗

Detecting disease gene in DNA haplotype sequences by nonparametric dissimilarity test.

Association studies for complex diseases based on haplotype data have received increasing attention in the last few years. A commonly used nonparametric method, which takes haplotype structure into consideration, is to use the U-statistic to compare the similarities between genetic compositions in the case and control populations. Although the method and its variants are convenient to use in practice, there are some areas where the tests cannot detect even large differences between cases and controls. To overcome this problem and enhance the power, we propose a new form of the weighted U-statistic, which directly compares the dissimilarity between the haplotype structures in the case and control populations. We show that this test statistic is asymptotically a linear combination of the absolute values of normal random variables under the null hypothesis, and shifts strictly toward the right under the alternative, and therefore has no blind areas of detection. Simulation studies indicate that our test statistic overcomes the weakness of the existing ones and is robust and powerful as well.

Base Sequence↗

Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects.

OBJECTIVES: To investigate the effects of darifenacin controlled-release (CR) and oxybutynin extended-release (ER) on cognitive function (particularly memory) in older subjects. METHODS: Healthy subjects (n=150) >/=60 years were randomised to darifenacin, oxybutynin ER or placebo in a multicentre, double-blind, double-dummy, parallel-group, 3-week study. Doses were administered according to US labels: oxybutynin ER 10mg once daily (od), increasing to 15mg od then 20mg od by week 3; darifenacin 7.5mg od in weeks 1 and 2, then 15mg od in week 3. The primary end point was accuracy on the Name-Face Association Test (delayed recall) at week 3. RESULTS: Results of the Name-Face Association Test at week 3 showed no significant difference between darifenacin and placebo on delayed recall (mean difference, -0.06, p=0.908). In contrast, oxybutynin ER resulted in memory impairment, with significantly lower scores than placebo and darifenacin (mean differences, -1.30, p=0.011 and -1.24, p=0.022, respectively) for delayed recall on the Name-Face Association Test at week 3. Additional tests of delayed recall indicated significant memory impairment with oxybutynin ER versus placebo at certain time points, whereas darifenacin was similar to placebo. No between-treatment differences were detected in self-rated memory, demonstrating that subjects were unaware of memory deterioration. CONCLUSIONS: While darifenacin had no significant effects on memory versus placebo, oxybutynin ER caused significant memory deterioration (magnitude of effect comparable to brain aging of 10 years). The results also demonstrate that subjects may not recognise/report memory deterioration.

Aged↗

Power comparison of two-sided exact tests for association in 2 x 2 contingency tables using standard, mid p and randomized test versions.

Exact Pearson's chi square, likelihood ratio (LR), and Fisher's tests are obtained from the conditional distribution of its test statistic, given the row and column sums of the contingency table. The power and obtained significance level of the standard, mid p, and randomized versions of these tests are compared for two-sided tests in 2 x 2 tables, using binomial and multinomial sampling. The mid p type I error probabilities seldom exceed the nominal significance level. The mid p and randomized test versions have approximately the same power, and higher power than the standard test version. The power of the Pearson's chi square, LR and Fisher's test differ, and they differ in approximately the same way for standard, mid p and randomized test versions for any given set of parameters. There is no general ranking between the three tests. In many cases, Pearson's chi square and Fisher's tests have almost equal power, and higher power than LR. In a few cases, perhaps characterized by poorly balanced designs, LR performs best. Fisher's test seems to be slightly more robust even if the design is poor.

Binomial Distribution↗

Test of association between TaqIA A1 allele and alcohol use disorder phenotypes in a sample of adolescent patients with serious substance and behavioral problems.

UNLABELLED: Several studies have demonstrated a significant association between the A1 allele of the TaqIA polymorphism and various phenotypes of alcoholism, others have not, and two studies have shown the reversed association, where the A2 allele was associated with higher levels of alcohol consumption. We sought to test for an association between early onset (in childhood or adolescence) alcohol use disorders and the DRD2 TaqIA polymorphism and to resolve some of the hypothesized explanations for previous negative results, utilizing a larger sample than many previous studies. METHODS: We selected individuals with a lifetime alcohol abuse or dependence (n=239) diagnosis from a clinically ascertained sample of youth (ages 13-19) with serious conduct and substance problems (about 90% also met criteria for conduct disorder and a cannabis use disorder) and compared them with individuals without a lifetime alcohol use disorder diagnosis ascertained from (1) community adolescent controls (n=151), (2) siblings of patients (n=87) and (3) other adolescent patients (n=92). Cases were compared with each control group, separately, by genotype using the chi(2)-test. Using 78 adolescent patients with an alcohol use disorder where genotypic information was available for both parents, we conducted the transmission disequilibrium test (TDT). RESULTS: Case-control results were non-significant using the entire community control sample (chi(2)(2)=1.92; p=0.38) and when restricting the sample to Caucasians (chi(2)(2)=3.81; p=0.15) or Hispanics (chi(2)(2)=1.70; p=0.43). Case-control results using the other comparison groups and TDT results were also non-significant. DISCUSSION: We did not find support for an association between the TaqIA polymorphism and early onset alcohol use disorders.

Adolescent↗

Evaluation of word associations as a reliable postoperative indicator of implicit memory formation during the intraoperative period.

Patients expect to receive an anesthetic that prevents the formation of memories during the intraoperative period. Unfortunately, explicit memory formation occurs 40,000 times per year in the United States, while the incidence of implicit memory is thought to be greater. The purpose of the study was to evaluate the effectiveness of word associations as a reliable postoperative indicator of implicit memory formation during the intraoperative period. Forty-eight participants scheduled to undergo general anesthesia for an elective procedure were selected. During the administration of 0.77 +/- .18 microgram/kg per minute of remifentanyl and 0.31 +/- .04 end-tidal volume percent of sevoflurane in air/oxygen, word associations in the form of "Trivial Pursuit" (Hasbro, Inc, Pawtucket, RI) game statements were presented via headphones. Within 24 hours of surgery, each participant was given a postoperative word association test that included the experimental and control word associations. No reports of explicit memory were noted. The experimental word associations were correctly answered 19.3% of the time, while the control word associations were correctly answered 12.8% of the time (P = .014). The findings illustrated that the word association test in the form of Trivial Pursuit game statements/answers may serve as a reliable postoperative indicator of implicit memory formation during the intraoperative period.

Adult↗

Testing the association between polymorphic markers and quantitative traits in pedigrees.

A statistical model that uses an iterative maximum likelihood estimation procedure is proposed for measuring and testing the association between polymorphic genetic markers and quantitative traits in human pedigrees, after adjusting for covariates such as age and sex. The model allows the quantitative trait to have a familial correlation structure among the individuals in the sample and to follow one of a broad class of skewed or kurtotic underlying distributions. The use of the model is illustrated, and the results are compared to those using models that assume normality without any transformation and do not incorporate familial correlations.

Analysis of Variance↗

Ability of laboratory methods to predict in-use efficacy of antimicrobial preservatives in an experimental cosmetic.

The abilities of nine antimicrobial systems to preserve an experimental water-based cosmetic formulation were evaluated by six microbiological challenge tests: the U.S. Pharmacopeia test; the British Pharmacopeia test; the Cosmetic, Toiletry, and Fragrance Association test; the rapid screen test; the sequential challenge test; and the post-use test. The antimicrobial systems contained various combinations and amounts of two parabens and a quaternary compound in order to provide a broad range of preservation. The results obtained were compared with the abilities of the formulations to support maintenance and growth of microorganisms in microfloras obtained from human axilla areas and finger skin during an 8-week simulated in-use test. Without statistical analysis all of the tests predicted the results obtained with well-preserved or poorly preserved formulations. The rapid screen test was the best test for predicting differences at intermediate levels of preservation. Statistically, all of the tests were equivalent predictors of preservation efficacy in the in-use test (P = 0.05). At the P = 0.10 level, only the U.S. Pharmacopeia, British Pharmacopeia, rapid screen, Cosmetic, Toiletry, and Fragrance Association tests were significantly predictive. The results of prediction by a test, based on the preservative levels used, agreed well with the in-use test results (P = 0.01). A total of 20% of the formulations that contained excessive microbial levels contained human axilla microorganisms. The levels of preservation in failed products were similar to the levels of preservation in unused controls.

Axilla↗

Prospectively validated predictions of shock and organ failure in individual septic surgical patients: the Systemic Mediator Associated Response Test.

INTRODUCTION: Clinically useful predictions of end-organ function and failure in severe sepsis may be possible through analyzing the interactions among demographics, physiologic parameters, standard laboratory tests, and circulating markers of inflammation. The present study evaluated the ability of such a methodology, the Systemic Mediator Associated Response Test (SMART), to predict the clinical course of septic surgery patients from a database of medical and surgical patients with severe sepsis and/or septic shock. PATIENTS AND METHODS: Three hundred and three patients entered into the placebo arm of a multi-institutional sepsis study were randomly assigned to a model-building cohort (n = 200; 119 surgical) or to a predictive cohort (n = 103; 55 surgical). Using baseline and baseline plus serial measurements of physiologic data, standard laboratory tests, and plasma levels of IL-6, IL-8, and granulocyte colony-stimulating factor (GCSF), multivariate models were developed that predicted the presence or absence of pulmonary edema on chest radiography, and respiratory, renal, coagulation, hepatobiliary, or central nervous system dysfunction and shock in individual patients. Twenty-eight-day survival was predicted also in baseline plus serial data models. These models were validated prospectively by inserting baseline raw data from the 55 surgical patients in the predictive cohort into the models built on the comprehensive training cohort, and calculating the area under the curve (AUC) of predicted versus observed receiver operator characteristic (ROC) plots. RESULTS: SMART predictions of physiologic, respiratory, metabolic, hepatic, renal, and hematologic function indicators were validated prospectively, frequently at clinically useful levels of accuracy. ROC AUC values above 0.700 were achieved in 30 out of 49 (61%) of SMART baseline models in predicting shock and organ failure up to 7 days in advance, and in 30 out of 54 (56%) of baseline plus serial data models. CONCLUSION: SMART multivariate models accurately predict pathophysiology, shock, and organ failure in individual septic surgical patients. These prognostications may facilitate early treatment of end-organ dysfunction in surgical sepsis.

Comorbidity↗

The v-MFG test: investigating maternal, offspring and maternal-fetal genetic incompatibility effects on disease and viability.

The MFG test is a family-based association test that detects genetic effects contributing to disease in offspring, including offspring allelic effects, maternal allelic effects and MFG incompatibility effects. Like many other family-based association tests, it assumes that the offspring survival and the offspring-parent genotypes are conditionally independent provided the offspring is affected. However, when the putative disease-increasing locus can affect another competing phenotype, for example, offspring viability, the conditional independence assumption fails and these tests could lead to incorrect conclusions regarding the role of the gene in disease. We propose the v-MFG test to adjust for the genetic effects on one phenotype, e.g., viability, when testing the effects of that locus on another phenotype, e.g., disease. Using genotype data from nuclear families containing parents and at least one affected offspring, the v-MFG test models the distribution of family genotypes conditional on offspring phenotypes. It simultaneously estimates genetic effects on two phenotypes, viability and disease. Simulations show that the v-MFG test produces accurate genetic effect estimates on disease as well as on viability under several different scenarios. It generates accurate type-I error rates and provides adequate power with moderate sample sizes to detect genetic effects on disease risk when viability is reduced. We demonstrate the v-MFG test with HLA-DRB1 data from study participants with rheumatoid arthritis (RA) and their parents, we show that the v-MFG test successfully detects an MFG incompatibility effect on RA while simultaneously adjusting for a possible viability loss.

Alleles↗

Using the Extrinsic Affective Simon Test as a measure of implicit attitudes towards alcohol: relationship with drinking behavior and alcohol problems.

In apparent contrast to the alleged importance of positive alcohol expectancies in alcohol (ab)use, a series of studies using the Implicit Association Test (IAT; [Greenwald, A. G., McGhee, D. E., & Schwartz, J.L.K. (1998). Measuring individual differences in implicit cognition: The Implicit Association Test. Journal of Personality and Social Psychology, 74, 1464-1480]), found that heavy and light drinkers display more negative implicit attitudes toward alcohol than toward sodas (e.g., [Wiers, R. W., van Woerden, N., Smulders, F. T. Y., & de Jong, P. J. (2002). Implicit and explicit alcohol-related cognitions in heavy and light drinkers. Journal of Abnormal Psychology, 111, 648-658]). One explanation for this might be that the negative-alcohol IAT effect reflects an artifact of the IAT procedure and are due to its relative nature and/or its sensitivity to task recoding strategies. Therefore, the present study used a non-relative measure that has been argued to be robust against participants' task recoding strategies (Extrinsic Affective Simon Test; EAST, [De Houwer, J. (2001). A structural and process analysis of the Implicit Association Test. Journal of Experimental Social Psychology, 37, 443-451]) to test heavy (n=16) and light (n=16) drinkers' automatic affective associations with alcohol and sodas. Heavy and light drinkers displayed clear positive associations with sodas and neutral (or ambivalent) automatic associations with alcohol. Importantly, positive automatic alcohol associations predicted unique variance of alcohol (mis)use and was the single best predictor of individuals' alcohol problems, underlining the idea that they do play a role in alcohol (mis)use.

Adult↗

Protein S assays: an analysis of North American Specialized Coagulation Laboratory Association proficiency testing.

To assess current laboratory practice and the performance of different reagent-instrument combinations for protein S testing, protein S results from the North American Specialized Coagulation Laboratory Association (NASCOLA) proficiency testing surveys for 2002 and the first half of 2003 were analyzed. A written survey of NASCOLA laboratories also was performed to further assess current laboratory practices for protein S testing. The free protein S antigen assays and the Diagnostica Stago Staclot protein S assay were extremely accurate in detecting a heterozygous type I protein S deficiency. Another functional protein S assay and most total protein S assays were less reliable, depending to some extent on the instrument. All assays used by NASCOLA laboratories appropriately identified normal protein S specimens. NASCOLA laboratories performed at least as well as European Concerted Action on Thrombosis laboratories in the proficiency tests. The results suggest that the diagnosis of heterozygous protein S deficiency may be problematic with some currently available assays. Many total protein S antigen assays do not add to the diagnosis and can be unreliable for protein S deficiency subtyping. Better standardization of functional and antigenic assays is needed.

Biological Assay↗

Score tests for association between traits and haplotypes when linkage phase is ambiguous.

A key step toward the discovery of a gene related to a trait is the finding of an association between the trait and one or more haplotypes. Haplotype analyses can also provide critical information regarding the function of a gene; however, when unrelated subjects are sampled, haplotypes are often ambiguous because of unknown linkage phase of the measured sites along a chromosome. A popular method of accounting for this ambiguity in case-control studies uses a likelihood that depends on haplotype frequencies, so that the haplotype frequencies can be compared between the cases and controls; however, this traditional method is limited to a binary trait (case vs. control), and it does not provide a method of testing the statistical significance of specific haplotypes. To address these limitations, we developed new methods of testing the statistical association between haplotypes and a wide variety of traits, including binary, ordinal, and quantitative traits. Our methods allow adjustment for nongenetic covariates, which may be critical when analyzing genetically complex traits. Furthermore, our methods provide several different global tests for association, as well as haplotype-specific tests, which give a meaningful advantage in attempts to understand the roles of many different haplotypes. The statistics can be computed rapidly, making it feasible to evaluate the associations between many haplotypes and a trait. To illustrate the use of our new methods, they are applied to a study of the association of haplotypes (composed of genes from the human-leukocyte-antigen complex) with humoral immune response to measles vaccination. Limited simulations are also presented to demonstrate the validity of our methods, as well as to provide guidelines on how our methods could be used.

Algorithms↗

Early pregnancy diagnosis in sheep by progesterone and pregnancy-associated glycoprotein tests.

The aim of this study was to compare the accuracy of the progesterone (P4) and pregnancy associated glycoprotein (PAG) tests for determination of early pregnancy in sheep. Estrus was synchronized in 182 Awassi x Merino ewes and blood samples were collected at Days 0 (day of the insemination), 18, 22, 29, 36, and 50 after artificial insemination (AI). Plasma P4 concentrations at Days 0 and 18 were determined by double antibody radioimmunoassay, while PAG concentrations at Days 22, 29, 36 and 50 were determined by a heterologous, double-antibody radioimmunoassay (RIA) using the bovine PAG 67 kDa subunit as tracer and standard and rabbit antiserum raised against a mixture of caprine 55 and 59 kDa PAG subunits as the first antibody. The discriminatory value for diagnosis of pregnancy by the P4 and the PAG-RIA tests was > or = 1 ng/ml. Based on lambing data, the accuracy for diagnosing pregnant (sensitivity) and non-pregnant ewes (specificity) and predictivity of both tests were calculated. The sensitivity, specificity, positive and negative predictive values for P4 and PAG tests were 100, 95.4, 81.6, and 100% at Day 18 (P4) and 93.5, 100, 100 and 98.7% at Day 22 (PAG), respectively. For diagnosis of non-pregnant ewes the PAG test had significantly higher specificity than the P4 test (P < 0.05). It is concluded that ovine pregnancy can be reliably diagnosed at Day 22 after AI by using a heterologous radioimmunoassay of PAG.

Animals↗

Significant sex differences in the correlation of electrocardiographic exercise testing and coronary arteriograms.

Two hundred fifty-one patients (195 male and 56 females) referred for evaluation of chest pain were studied by multistage submaximal stress testing and selective coronary arteriography. In men with positive exercise tests the incidence rate of true positive exercise test results--that is, positive tests associated with 75 percent of greater coronary stenosis--was 89 percent in contrast to a 33 percent incidence rate of true positive exercise test results in women. The incidence rate of false positive excercise test results--that is, positive tests associated with no coronary stenosis or less than 50 percent stenosis--was 8 percent in men in contrast to 67 percent in women. Conversely, the incidence rate of false negative exercise test results (that is, negative exercise tests associated with 75 percent or greater coronary stenosis) was higher in men (37 percent) than in women (12 percent). It is concluded that in men a positive multistage stress test is useful in predicting the presence of significant coronary artery disease although a negative stress test cannot be relied upon to rule out the presence of significant disease. In women, a positive exercise test is of little value in predicting the presence of significant coronary artery disease, whereas a negative test is quite useful in ruling out the presence of significant disease. New criteria should be developed for stress testing of women.

Adult↗

The use of the bladder-tumour associated analyte test to determine the type of cystoscopy in the follow-up of patients with bladder cancer. The United Kingdom and Eire Bladder Tumour Antigen Study Group.

OBJECTIVE: To assess the use of the bladder-tumour associated analyte test (BTA, Bard UK) to determine whether patients with bladder cancer scheduled for cystoscopy under general anaesthesia can have local anaesthesia instead. PATIENTS AND METHODS: A total of 272 patients who were scheduled for general anaesthesia cystoscopy were entered into a prospective multicentre study. The BTA test was performed on a specimen of freshly voided urine and the type of cystoscopy was determined according to whether the result was positive or negative. Patients with a negative BTA result were examined with the flexible instrument, under local anaesthesia, instead of the planned general anaesthetic cystoscopy. RESULTS: In 59 patients, the BTA test was positive and tumour was found (true positive), in 145 patients the test was negative and cystoscopy was negative (true negative), in 25 patients the test was positive and cystoscopy was negative (false positive) and in 43 patients, the test was negative but tumour was found on flexible cystoscopy; the patient underwent subsequent cystoscopy under general anaesthesia (false negative). The sensitivity and specificity were 58% and 86% respectively. The use of the BTA test resulted in fewer patients needing cystoscopy under general anaesthesia and saved about 25,500 POUNDS ($31,000) OR 76 POUNDS ($114) PER PATIENT. CONCLUSION: THE integration of the BTA test into the follow-up of patients with bladder cancer may help to select those suitable for cystoscopy, under a local anaesthetic and this will result in cost savings as well as sparing patients the more invasive procedure. The test is not sufficiently sensitive to replace cystoscopy and there were false-negative results despite high-grade recurrence. Thus, when the test is used as part of a follow-up programme, a timely back-up of cystoscopy under general anaesthesia should be arranged for patients with false-negative results.

Anesthesia, General↗