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PubMed2005

The impact of diagnostic error on testing genetic association in case-control studies.

In case-control studies, subjects in the case group may be recruited from suspected patients who are diagnosed positively with disease. While many statistical methods have been developed for measurement error or misclassification of exposure variables in epidemiological studies, no studies have been reported on the effect of errors in diagnosing disease on testing genetic association in case-control studies. We study the impact of using the original Cochran-Armitage trend test assuming no diagnostic error when, in fact, cases and controls may be clinically diagnosed by an imperfect gold standard or a reference test. The type I error, sample size and asymptotic power of trend tests are examined under a family of genetic models in the presence of diagnostic error. The empirical powers of the trend tests are also compared by simulation studies under various genetic models.

Case-Control Studies↗

PubMed2005

Nonparametric tests of association of multiple genes with human disease.

The genetic basis of many common human diseases is expected to be highly heterogeneous, with multiple causative loci and multiple alleles at some of the causative loci. Analyzing the association of disease with one genetic marker at a time can have weak power, because of relatively small genetic effects and the need to correct for multiple testing. Testing the simultaneous effects of multiple markers by multivariate statistics might improve power, but they too will not be very powerful when there are many markers, because of the many degrees of freedom. To overcome some of the limitations of current statistical methods for case-control studies of candidate genes, we develop a new class of nonparametric statistics that can simultaneously test the association of multiple markers with disease, with only a single degree of freedom. Our approach, which is based on U-statistics, first measures a score over all markers for pairs of subjects and then compares the averages of these scores between cases and controls. Genetic scoring for a pair of subjects is measured by a "kernel" function, which we allow to be fairly general. However, we provide guidelines on how to choose a kernel for different types of genetic effects. Our global statistic has the advantage of having only one degree of freedom and achieves its greatest power advantage when the contrasts of average genotype scores between cases and controls are in the same direction across multiple markers. Simulations illustrate that our proposed methods have the anticipated type I-error rate and that they can be more powerful than standard methods. Application of our methods to a study of candidate genes for prostate cancer illustrates their potential merits, and offers guidelines for interpretation.

Case-Control Studies↗

PubMed2004

A haplotype-based test of association using data from cohort and nested case-control epidemiologic studies.

Haplotype-based risk models can lead to powerful methods for detecting the association of a disease with a genomic region of interest. In population-based studies of unrelated individuals, however, the haplotype status of some subjects may not be discernible without ambiguity from available locus-specific genotype data. A score test for detecting haplotype-based association using genotype data has been developed in the context of generalized linear models for analysis of data from cross-sectional and retrospective studies. In this article, we develop a test for association using genotype data from cohort and nested case-control studies where subjects are prospectively followed until disease incidence or censoring (end of follow-up) occurs. Assuming a proportional hazard model for the haplotype effects, we derive an induced hazard function of the disease given the genotype data, and hence propose a test statistic based on the associated partial likelihood. The proposed test procedure can account for differential follow-up of subjects, can adjust for possibly time-dependent environmental co-factors and can make efficient use of valuable age-at-onset information that is available on cases. We provide an algorithm for computing the test statistic using readily available statistical software. Utilizing simulated data in the context of two genomic regions GPX1 and GPX3, we evaluate the validity of the proposed test for small sample sizes and study its power in the presence and absence of missing genotype data.

Algorithms↗

PubMed2006

Nasal airflow recovery after decongestion test is associated with bronchial hyperreactivity in patients with allergic rhinitis.

BACKGROUND: The decongestion test involves spraying an intranasal vasoconstrictor drug to evaluate the recovery of nasal airflow. OBJECTIVE: The aim of this study was to assess the relationship between pulmonary function (assessed by spirometry and methacholine challenge) and nasal airflow recovery after a topical vasoconstrictor had been administered in patients with allergic rhinitis (perennial, seasonal, or mixed allergic rhinitis). METHODS: A total of 150 subjects were studied. The total symptom score, sensitization, and pulmonary function were all assessed. All subjects underwent rhinomanometry and the decongestion test. RESULTS: Univariate analysis revealed that nasal symptoms and spirometric parameters (except FEF(25-75) in subjects with seasonal allergic rhinitis) were not. Only bronchial hyperreactivity, assessed by methacholine challenge, proved to be significantly (and independently) associated with outcome (OR 1.45, P = 0.025). CONCLUSIONS: This study provides the first evidence of an association between a positive response to the decongestion test and bronchial hyperreactivity, assessed by methacholine challenge, in patients with allergic rhinitis.

Adult↗

PubMed2000

Prospectively validated prediction of organ failure and hypotension in patients with septic shock: the Systemic Mediator Associated Response Test (SMART).

Conventional outcomes research provides only percentage risk categories that are not applicable to individual patients, and it predicts only mortality, utilization of resources and/or broad groupings of multiple organ system dysfunction. The purpose of the present study was to determine whether or not the Systemic Mediator Associated Response Test (SMART) methodology could identify interactions among demographics, physiologic parameters, standard hospital laboratory tests, and circulating cytokine concentrations to predict continuous and dichotomous dependent clinical variables, in advance, in individual patients with septic shock and to integrate these into prospectively validated models. Two hundred forty (240) patients with septic shock who were entered into the placebo arm of a multi-institutional clinical trial were randomly separated into a model building training cohort (n = 154) and a predictive cohort (n = 86), which was used to prospectively validate the prognostic models built upon the training cohort database. From baseline patient demographics; hospital laboratory tests; and plasma levels of interleukin-6, interleukin-8, and granulocyte colony stimulating factor, multiple regression models were developed that predicted clinically important continuous dependent variables quantitatively in individual patients. Multivariate stepwise logistic regression was utilized to develop models that prognosticated dichotomous dependent end points. At the completion of the modeling process, baseline data from individual patients in the predictive cohort was inserted into each multivariate model for each day. Prospective validation was accomplished by simple linear regression of individual predicted versus observed values for continuous dependent variables, and by establishing the Receiver Operator Characteristics Area Under the Curve (ROC AUC) for logistic regression models that predicted dichotomous end points. Through seven days, SMART quantitative predictions of selected physiologic and metabolic parameters were validated at r > 0.500 in 51%. Up to seven days after baseline, 31/49 (63%) SMART models for renal and liver function indicators were validated prospectively at the r > 0.700 level. For hematologic/coagulation models, 37/56 (66%) up to seven days had r > 0.900. Among dichotomous models, ROC AUC > 0.700 was achieved in 30/49 (61%) during the first week. SMART integration of demographics, bedside physiology, hospital laboratory tests, and circulating cytokines predicts organ failure and physiologic function indicators in individual patients with septic shock.

Area Under Curve↗

PubMed1995

Exact tests for association between alleles at arbitrary numbers of loci.

Associations between allelic frequencies, within and between loci, can be tested for with an exact test. The probability of the set of multi-locus genotypes in a sample, conditional on the allelic counts, is calculated from multinomial theory under the hypothesis of no association. Alleles are then permuted and the conditional probability calculated for the permuted genotypic array. The proportion of arrays no more probable than the original sample provides the significance level for the test. An algorithm is provided for counting genotypes efficiently in the arrays, and the powers of the test presented for various kinds of association. The powers for the case when associations are generated by admixture of several populations suggest that exact tests are capable of detecting levels of association that would affect forensic calculations to a significant extent.

Algorithms↗

PubMed2002

Prospectively validated prediction of physiologic variables and organ failure in septic patients: The Systemic Mediator Associated Response Test (SMART).

OBJECTIVE: Conventional outcomes research provides only percentage risk of such end points as mortality rate, utilization of resources, and/or broad groupings of multiple organ system dysfunction. These prognostications generally are not applicable to individual patients. The purpose of the present study was to determine whether the Systemic Mediator Associated Response Test (SMART) methodology could identify interactions among demographics, physiologic variables, standard hospital laboratory tests, and circulating cytokine concentrations that predicted continuous and dichotomous dependent clinical variables, in advance, in individual patients with severe sepsis and septic shock, and whether these independent variables could be integrated into prospectively validated predictive models. DESIGN: Data review and multivariate stepwise logistic regression. SETTING: University research laboratory. PATIENTS: Three hundred three patients with severe sepsis or septic shock who comprised the placebo arm of a multiple-institution clinical trial, who were randomly separated into a model building training cohort (n = 200) and a predictive cohort (n = 103). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From baseline data and baseline plus serial input, including patient demographics, hospital laboratory tests, and plasma concentrations of interleukin-6, interleukin-8, and granulocyte colony stimulating factor, multiple regression models were developed that predicted clinically important continuous dependent variables quantitatively, in individual patients. Multivariate stepwise logistic regression was used to develop models that prognosticated dichotomous dependent end points. Data from individual patients in the predictive cohort were inserted into each predictive model for each day, with prospective validation accomplished by simple linear regression of individual predicted vs. observed values for continuous dependent variables, and by establishing the receiver operator characteristics area under the curve for logistic regression models that predicted dichotomous end points. Of SMART models for continuous dependent variables, 100 of 143 (70%) were validated at r values >.7 through day 3, and 184 of 259 (71%) above r =.5 through day 5. SMART predictions of dichotomous end points achieved receiver operator characteristics areas under the curve >.7 for up to 84% of the equations in the first week. Many SMART models for both continuous and dichotomous dependent variables were validated at clinically useful levels of accuracy as far as 28 days after baseline. CONCLUSIONS: SMART integration of demographics, bedside physiology, hospital laboratory tests, and circulating cytokines predicts organ failure and physiologic function indicators in individual patients with severe sepsis and septic shock.

Clinical Laboratory Techniques↗

PubMed2003

On a semiparametric test to detect associations between quantitative traits and candidate genes using unrelated individuals.

Although genetic association studies using unrelated individuals may be subject to bias caused by population stratification, alternative methods that are robust to population stratification such as family-based association designs may be less powerful. Recently, various statistical methods robust to population stratification were proposed for association studies, using unrelated individuals to identify associations between candidate markers and traits of interest (both qualitative and quantitative). Here, we propose a semiparametric test for association (SPTA). SPTA controls for population stratification through a set of genomic markers by first deriving a genetic background variable for each sampled individual through his/her genotypes at a series of independent markers, and then modeling the relationship between trait values, genotypic scores at the candidate marker, and genetic background variables through a semiparametric model. We assume that the exact form of relationship between the trait value and the genetic background variable is unknown and estimated through smoothing techniques. We evaluate the performance of SPTA through simulations both with discrete subpopulation models and with continuous admixture population models. The simulation results suggest that our procedure has a correct type I error rate in the presence of population stratification and is more powerful than statistical association tests for family-based association designs in all the cases considered. Moreover, SPTA is more powerful than the Quantitative Similarity-Based Association Test (QSAT) developed by us under continuous admixture populations, and the number of independent markers needed by SPTA to control for population stratification is substantially fewer than that required by QSAT.

Analysis of Variance↗

PubMed2005

Self-esteem and depression revisited: implicit positive self-esteem in depressed patients?

The cognitive behavioural model of depression holds that negative cognitions related to the self have etiological importance for the maintenance and relapse of depression. This has been confirmed by research using questionnaires. Recent research using the Implicit Association Test, however, showed positive implicit self-esteem in formerly depressed participants, even after negative mood induction [Gemar, Segal, Sagrati, & Kennedy (2001). Mood-induced changes on the implicit association test in recovered depressed patients. Journal of Abnormal Psychology, 110, 282-289]. These results are not in line with cognitive theory of depression. Since this could be an artifact of the specific procedure that was used, we investigated implicit self-esteem of currently depressed participants and healthy controls using three different paradigms: The Implicit Association Test, the Name Letter Preference Task, and the Extrinsic Affective Simon Task. The results of the three experiments are unequivocally indicative of positive implicit self-esteem in currently depressed patients. However, it remains an intriguing question what exactly these indirect measures assess.

Adult↗

PubMed2006

Incorporating serotypes into family based association studies using the MFG test.

Family based association tests are widely used to detect genetic effects. The focus of this paper is the maternal-fetal genotype (MFG) incompatibility test, a family based association test which can be used to detect genetic effects that contribute to disease, including alleles in the child that increase disease risk, maternal alleles that increase disease risk in the child, and maternal-fetal genotype incompatibilities. Consideration of incomplete data resulting from using serotypes could expand the power of the MFG test for detecting genetic effects. Serotypes may be all that are available in certain families, or preferred because of convenience or low cost, and thus a modification of the MFG test will allow optimal use of such data. The modified MFG likelihood can accommodate the incomplete data that result from using serotypes rather than the corresponding codominant genotypes. The modified MFG test was evaluated with serotypes and genotypes from families with members affected with schizophrenia. In addition, simulation studies were performed. Results of the data analyses and simulation studies showed that serotypes can be used to augment genotypes within a sample, to increase power to detect effects when the candidate gene produces serotypes.

Blood Group Incompatibility↗

PubMed1975

Tests for association of gene frequencies at several loci in random mating diploid populations.

Methods are outlined for analyzing data on genotype frequencies at several codominant loci in random mating diploid populations. Maximum likelihood (ML) methods are given for estimating chromosomal frequencies. Using these, a succession of models of assumed independence of gene frequency are fitted. These are based on those used in multi-dimensional contigency tables, and tests for association (linkage disequilibrium), made using likelihood ratios. The methods are illustrated with an example.

Diploidy↗

PubMed2005

New joint covariance- and marginal-based tests for association and linkage for quantitative traits for random and non-random sampling.

We develop novel statistical tests for transmission disequilibrium testing (tests of linkage in the presence of association) for quantitative traits using parents and offspring. These joint tests utilize information in both the covariance (or more generally, dependency) between genotype and phenotype and the marginal distribution of genotype. Using computer simulation we test the validity (Type I error rate control) and power of the proposed methods, for additive, dominant, and recessive modes of inheritance, locus-specific heritability of the trait 0.05, 0.1, 0.2 with allele frequencies of P=0.2 and 0.4, and sample sizes of 500, 200, and 100 trios. Both random sampling and extreme sampling schemes were investigated. A multinomial logistic joint test provides the highest overall power irrespective of sample size, allele frequency, heritability, and modes of inheritance.

Algorithms↗

PubMed1996

Partitioned association-linkage test: distinguishing "necessary" from "susceptibility" loci.

Marker allele-disease association and linkage between a disease locus and a marker locus are two different phenomena. Linkage without evidence of association and association without evidence of linkage are possible observations. Linkage analysis uses marker loci and the phenomenon of recombination to look for disease-related loci which are presumably major contributors to disease expression ("necessary" loci). However, the phenomenon of association is more complex. One explanation for the existence of an association is that there is a "necessary" locus in linkage disequilibrium with a marker locus. Another explanation is that the marker locus itself (or a closely linked locus in linkage disequilibrium with the marker) is a "susceptibility" locus, which increases the probability of contracting the disease but is not necessary for disease expression. Although there are other possible explanations for the existence of an association, these two can lead to different results when family data from a disease showing association are analyzed for linkage between the associated marker and the disease. If the linkage disequilibrium hypothesis is correct, there will be evidence for linkage. If the susceptibility locus hypothesis is correct, there may be strong evidence against linkage. In this work, we explore a method that could indicate whether an association is due to a susceptibility locus or a necessary locus. We show that, by dividing families based on the presence or absence of the associated marker allele in a randomly chosen affected sib, calculating lod scores, and then calculating a heterogeneity statistic, we could distinguish whether linkage data came from a susceptibility locus or a necessary locus.

Alleles↗

PubMed2001

Implicit attitude measures: consistency, stability, and convergent validity.

In recent years, several techniques have been developed to measure implicit social cognition. Despite their increased use, little attention has been devoted to their reliability and validity. This article undertakes a direct assessment of the interitem consistency, stability, and convergent validity of some implicit attitude measures. Attitudes toward blacks and whites were measured on four separate occasions, each 2 weeks apart, using three relatively implicit measures (response-window evaluative priming, the Implicit Association Test, and the response-window Implicit Association Test) and one explicit measure (Modern Racism Scale). After correcting for interitem inconsistency with latent variable analyses, we found that (a) stability indices improved and (b) implicit measures were substantially correlated with each other, forming a single latent factor. The psychometric properties of response-latency implicit measures have greater integrity than recently suggested.

Adult↗

PubMed2003

Immune testing in fertility practice: truth or deception?

PURPOSE OF REVIEW: Much attention has been paid to the role of immunology in reproductive success or failure. Every step in the establishment of normal pregnancy has been implicated as a possible site of immune-mediated reproductive failure. The widespread testing of antiphospholipid, antinuclear, antithyroid, and antisperm antibodies, as well as generalized immune testing, have thus been employed to diagnose patients with otherwise unexplained infertility or recurrent pregnancy loss. Controversial data surrounding the widespread and variable use of immune testing in current fertility practice is reviewed to determine which tests are warranted based on sound scientific evidence. Because it is postulated that early miscarriage, when occult, could represent a failure of embryo implantation indistinguishable from unexplained infertility, this analysis of immune testing includes a discussion of patients with recurrent pregnancy loss. RECENT FINDINGS: Despite the increased prevalence of abnormal immune testing associated with early reproductive failure, the most rigorous studies have not proven a cause and effect between these phenomena. There is wide variation and inconsistency regarding this association, depending upon which test(s) are employed, the study methodology used, and the patient population under study. The significance of selected immunological test abnormalities associated with early reproductive failure is uncertain. SUMMARY: Great variability exists in identifying candidates for immune testing, determining which tests to order, interpreting the test results, and offering immunologic treatments. This review argues that the use of widespread immune testing in clinical practice can not be supported by existing data. The resulting therapies are similarly of unconfirmed benefit and may cause harm.

Antibodies, Antiphospholipid↗

PubMedDate not supplied

Liver dysfunction and energy source: results of a randomized clinical trial.

Controversy still exists regarding the role of the carbohydrate:fat ratio on liver function abnormalities associated with the administration of total parenteral nutrition (TPN). We designed a prospective clinical trail comparing standard carbohydrate-based TPN (8.5% amino acids, 50% dextrose, 7.5% of total calories from lipids) with an isocaloric lipid-based TPN (8.5% amino acids, 30% dextrose, 40% of total calories from lipids) in 43 patients exclusively receiving TPN > or = 2 weeks. Energy needs were calculated as basal energy expenditure x 1.5. The mean daily calorie intake for patients who obtained carbohydrate-based TPN (CHO) was 2227 kcal, whereas the lipid-based TPN (LIP-CHO) group achieved a mean of 2310 kcal. Patients with preexisting liver disease were excluded. There was no significant difference in age or diagnosis between the groups. We monitored total bilirubin, direct bilirubin, alkaline phosphatase, gamma-glutamyl transferase, lactic dehydrogenase, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase. Initial liver-associated tests did not vary significantly between groups. Group mean values after 2 weeks of TPN were significantly different for total bilirubin (1.5 mg/dL in the CHO group compared with 0.7 in the LIP-CHO group, p < .05) and direct bilirubin (0.8 mg/dL in the CHO group compared with 0.3 mg/dL in the mixed substrate group, p < .05). Differences in mean values between groups were also noted for serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and lactic dehydrogenase. In conclusion, this prospective trial reveals that the use of a balanced energy source TPN solution prevents the abnormalities in liver-associated tests commonly associated with TPN.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed2002

Linkage and association for bone mineral density and heel ultrasound measurements with a simple tandem repeat polymorphism near the osteocalcin gene in female dizygotic twins.

In this confirmatory candidate gene study, we investigated possible linkage and association for bone density, heel ultrasound and bone turnover with the osteocalcin gene using the nearby (50-180kb) microsatellite marker D1S3737. Non-identical twin sisters aged 18-75 years at first interview were recruited for the study from the St Thomas' UK Adult Twin Registry with 1366 women being genotyped for marker D1S3737. Linkage, allelic association and joint linkage and association tests were carried out using quantitative transmission disequilibrium tests (QTDT), along with post-hoc multivariate tests of linkage and association. Phenotypes tested were bone mineral density (BMD) at the spine, left forearm and left total hip; quantitative ultrasound measurements of the heel including velocity of ultrasound (VOS) and broadband ultrasound attenuation (BUA); and bone turnover markers, urine deoxypyridinoline (DPD), serum osteocalcin, bone specific and total alkaline phosphatase (ALP). BMD and ultrasound variables showed evidence of pleiotropic linkage ( p = 0.05) and association ( p = 0.02) with the marker in postmenopausal women. Bone markers showed little or no evidence of linkage and association for any age group. Evidence for pleiotropic linkage appeared to be strongest for BUA and spine BMD in postmenopausal women. The univariate test statistic for BUA was chi(2)(1)=12.8 ( p = 0.0003), equivalent to a LOD score of 2.8. DPD showed borderline evidence of linkage to the marker for women of all ages. Multivariate model-fitting showed allele 10 to be negatively associated with BMD, VOS and BUA via a common pathway, suggesting the putative functional polymorphism affects both bone content and structure through shared underlying metabolic pathways. It is likely that the alleles are in linkage disequilibrium with functional polymorphism(s) in or nearby the osteocalcin gene, which may contribute to the onset of osteoporosis.

Adult↗

PubMed1993

Assessment of changes in psychomotor performance of elderly subjects.

1. The repeatability of a computerised psychomotor test battery on a day-to-day and week-to-week basis was assessed by determining its test-retest reliability and variations in group-means and intraindividual psychomotor performance scores of elderly people. 2. Psychomotor performance was assessed in 50 well-screened elderly subjects (21 males, 29 females; mean age 70.4 +/- 5.0 (s.d.) years) on 5 consecutive days and over 4 weeks in standardised test conditions. 3. The psychomotor test battery consisted of computerised versions of symbol digit substitution test (SDST), continuous attention test (CAT), choice reaction time (CRT), critical flicker fusion test (CFFT), cognitive flexibility test (FLEX), paired word association test (PWAT) and inspection time (INSP). 4. Main outcome measures were test-retest reliability, group variability and intraindividual variability. 5. There was no significant variation in group-means for all components of the test battery over 5 days or 4 weeks on two way analysis of variance. The intraindividual coefficient of variation was low for SDST, CRT, CFFT, FLEX, PWAT and INSP during the period of assessment. Test retest reliability was greater than 0.8 for SDST, CAT, CRT and PWAT. 6. Tests in the Automated Psychomotor Test Battery are reliable and repeatable measures of psychomotor performance on a day-to-day and week-to-week basis.

Aged↗