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PubMed2003

Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease.

The cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene on 2q33 is associated with autoimmune thyroid diseases (AITDs). Our earlier study in 56 families showed linkage of 2q33 to the presence of thyroid antibodies (TAbs). The goals of this study were to confirm the linkage of the 2q33 region to TAbs, to fine map this region, and study the ICOS gene. We performed a linkage study in an expanded data set of 99 multiplex AITD-TAb families (529 individuals). The highest two-point LOD score of 2.9 was obtained for marker D2S325 on 2q33. To fine map this locus, we genotyped 238 Caucasian AITD patients and 137 controls for five additional markers in the linked locus, which contained the CTLA-4, CD28, and ICOS genes. The A/G single-nucleotide polymorphism at position 49 of CTLA-4 was associated with AITD (P=0.01, OR=1.5), while markers inside CD28 and ICOS were not. Functional studies have shown that the G allele was associated with reduced inhibition of T-cell proliferation by CTLA-4. We concluded that: (1) the AITD gene in the 2q33 locus is the CTLA-4 gene and not the CD28 or ICOS genes; and (2) the G allele is associated with decreased function of CTLA-4.

Alleles↗

PubMed1995

Smoking behaviors of women after diagnosis with lung cancer.

The purpose of this study was to describe the smoking behavior of women with a recent diagnosis or recurrence of lung cancer. A convenience sample of women (N = 65) participated in interviews about their smoking status, their perception of the effect of their diagnosis on the smoking behaviors of others, and self reports of symptom distress and functional status. Content analysis of the audiotapes was used to classify responses. Exemplars describe feelings related to smoking, smoking cessation, and responses of others. Current smokers were likely to be younger (F4.60 = 4.3, p < .05). In this small sample, symptom distress and functional status were not statistically differentiated by smoking status; current smokers had the greatest mean distress from cough. Diagnosis had a variable effect on the smoking behavior of family members with over 25% stopping smoking in response to the diagnosis; 31% of smoking spouses continued to smoke.

Aged↗

PubMed2003

Phylogenetic shadowing of primate sequences to find functional regions of the human genome.

Nonhuman primates represent the most relevant model organisms to understand the biology of Homo sapiens. The recent divergence and associated overall sequence conservation between individual members of this taxon have nonetheless largely precluded the use of primates in comparative sequence studies. We used sequence comparisons of an extensive set of Old World and New World monkeys and hominoids to identify functional regions in the human genome. Analysis of these data enabled the discovery of primate-specific gene regulatory elements and the demarcation of the exons of multiple genes. Much of the information content of the comprehensive primate sequence comparisons could be captured with a small subset of phylogenetically close primates. These results demonstrate the utility of intraprimate sequence comparisons to discover common mammalian as well as primate-specific functional elements in the human genome, which are unattainable through the evaluation of more evolutionarily distant species.

Animals↗

PubMed2003

Inflammatory markers and cognition in well-functioning African-American and white elders.

BACKGROUND: Several lines of evidence suggest that inflammatory mechanisms contribute to AD. OBJECTIVE: To examine whether several markers of inflammation are associated with cognitive decline in African-American and white well-functioning elders. METHODS: The authors studied 3,031 African-American and white men and women (mean age 74 years) enrolled in the Health, Aging, and Body Composition Study. Serum levels of interleukin-6 (IL-6) and C-reactive protein (CRP) and plasma levels of tumor necrosis factor-alpha (TNFalpha) were measured at baseline; cognition was assessed with the Modified Mini-Mental State Examination (3MS) at baseline and at follow-up. Cognitive decline was defined as a decline of >5 points. RESULTS: In age-adjusted analyses, participants in the highest tertile of IL-6 or CRP performed nearly 2 points lower (worse) on baseline and follow-up 3MS (p < 0.001 for all) and declined by almost 1 point over the >2 years (p = 0.01 for IL-6 and p = 0.04 for CRP) compared with those in the lowest tertile. After multivariate adjustment, 3MS scores among participants in the highest tertile of IL-6 and CRP were similar at baseline but remained significantly lower at follow-up (p < or = 0.05 for both). Those in the highest inflammatory marker tertile were also more likely to have cognitive decline compared with the lowest tertile for IL-6 (26 vs 20%; age-adjusted odds ratio [OR] = 1.34; 95% CI 1.06 to 1.69) and for CRP (24 vs 19%; OR = 1.41; 95% CI 1.10 to 1.79) but not for TNFalpha (23 vs 21%; OR = 1.12; 95% CI 0.88 to 1.43). There was no significant interaction between race and inflammatory marker or between nonsteroidal anti-inflammatory drug use and inflammatory marker on cognition. CONCLUSIONS: Serum markers of inflammation, especially IL-6 and CRP, are prospectively associated with cognitive decline in well-functioning elders. These findings support the hypothesis that inflammation contributes to cognitive decline in the elderly.

Black or African American↗

PubMed2006

Simple and multiple P-splines regression with shape constraints.

In many research areas, especially within social and behavioural sciences, the relationship between predictor and criterion variables is often assumed to have a particular shape, such as monotone, single-peaked or U-shaped. Such assumptions can be transformed into (local or global) constraints on the sign of the nth-order derivative of the functional form. To check for such assumptions, we present a non-parametric regression method, P-splines regression, with additional asymmetric discrete penalties enforcing the constraints. We show that the corresponding loss function is convex and present a Newton-Raphson algorithm to optimize. Constrained P-splines are illustrated with an application on monotonicity-constrained regression with both one and two predictor variables, using data from research on the cognitive development of children.

Algorithms↗

PubMed2004

Rapid evolution through gene duplication and subfunctionalization of the testes-specific alpha4 proteasome subunits in Drosophila.

Gene duplication is an important mechanism for acquiring new genes and creating genetic novelty in organisms. Evidence suggests that duplicated genes are retained at a much higher rate than originally thought and that functional divergence of gene copies is a major factor promoting their retention in the genome. We find that two Drosophila testes-specific alpha4 proteasome subunit genes (alpha4-t1 and alpha4-t2) have a higher polymorphism within species and are significantly more diverged between species than the somatic alpha4 gene. Our data suggest that following gene duplication, the alpha4-t1 gene experienced relaxed selective constraints, whereas the alpha4-t2 gene experienced positive selection acting on several codons. We report significant heterogeneity in evolutionary rates among all three paralogs at homologous codons, indicating that functional divergence has coincided with genic divergence. Reproductive subfunctionalization may allow for a more rapid evolution of reproductive traits and a greater specialization of testes function. Our data add to the increasing evidence that duplicated genes experience lower selective constraints and in some cases positive selection following duplication. Newly duplicated genes that are freer from selective constraints may provide a mechanism for developing new interactions and a pathway for the evolution of new genes.

Animals↗

PubMed1994

Backcalculation of the number infected with human immunodeficiency virus in Germany.

The method of backcalculation was used to estimate the cumulative number of human immunodeficiency virus type 1 (HIV-1)-infected adults in Germany from reporting delay-corrected surveillance data on acquired immunodeficiency syndrome (AIDS) in the pretreatment era. Using different backcalculation approaches with various incubation period distributions, a plausible range of 13,100 to 23,900 HIV-1-infected adults as of December 31, 1984, was calculated. Estimates of the number infected at more recent times were subject to much greater uncertainty. On average, the cumulative incidences calculated by the nonparametric backprojection method are about 15% lower than the results from the step function model. Nonparametric backprojection with the Hessol incubation distribution suggests a declining HIV infection rate after 1985, as might be expected from German health policies. This distribution is derived from cohorts of homosexual men, the main fraction of German AIDS cases.

Algorithms↗

PubMed1996

Polynomials with asymptotes for longitudinal data.

I use Laguerre polynomials to model growth curves or time--response curves known to approach an asymptote as time approaches infinity. An example is with measurements on a variable or variables from subjects recovering from surgery. These variables can often vary in a non-monotonic fashion for which a functional form of the curve is unknown. Using a longitudinal data mixed model, one can include in the model random subject effects, within-subject serial correlation and fixed or time varying covariates. I present two examples that involve groups of subjects recovering from surgery.

Anterior Cruciate Ligament↗

PubMed2002

Gene expression profiling in developing human hippocampus.

The gene expression profile of developing human hippocampus is of particular interest and importance to neurobiologists devoted to development of the human brain and related diseases. To gain further molecular insight into the developmental and functional characteristics, we analyzed the expression profile of active genes in developing human hippocampus. Expressed sequence tags (ESTs) were selected by sequencing randomly selected clones from an original 3'-directed cDNA library of 150-day human fetal hippocampus, and a digital expression profile of 946 known genes that could be divided into 16 categories was generated. We also used for comparison 14 other expression profiles of related human neural cells/tissues, including human adult hippocampus. To yield more confidence regarding differential expression, a method was applied to attach normalized expression data to genes with a low false-positive rate (<0.05). Finally, hierarchical cluster analysis was used to exhibit related gene expression patterns. Our results are in accordance with anatomical and physiological observations made during the developmental process of the human hippocampus. Furthermore, some novel findings appeared to be unique to our results. The abundant expression of genes for cell surface components and disease-related genes drew our attention. Twenty-four genes are significantly different from adult, and 13 genes might be developing hippocampus-specific candidate genes, including wnt2b and some Alzheimer's disease-related genes. Our results could provide useful information on the ontogeny, development, and function of cells in the human hippocampus at the molecular level and underscore the utility of large-scale, parallel gene expression analyses in the study of complex biological phenomena.

Adult↗

PubMed2005

Prenatal screening for congenital heart disease using real-time three-dimensional echocardiography and a novel 'sweep volume' acquisition technique.

OBJECTIVES: Conventional prenatal screening for congenital heart disease (CHD) involves a time-consuming and highly operator-dependent acquisition of the four-chamber view and outflow tracts. By acquiring the entire fetal heart instantaneously as a single volume, real-time three-dimensional echocardiography (RT3DE) may facilitate fetal cardiac screening. METHODS: Four reviewers, each experienced with fetal cardiac imaging, blindly and independently evaluated a single cardiac volume from each of 18 fetuses (11 normal, seven with CHD). Two-dimensional echocardiography served as the gold standard. Three-dimensional evaluation of each fetus included a series of volume acquisitions lasting 2-6 s each. A 'sweep volume' technique was developed to fit larger hearts into a single non-gated volume. RESULTS: RT3DE had a high sensitivity for detecting CHD (93%), with only a single case being missed by two observers. Specificity for CHD was low (45%), with a high rate of 'cannot determine' responses and false positive artifacts. CONCLUSIONS: These preliminary results suggest that RT3DE has the potential to function as a screening tool for fetal heart disease. However, artifacts must be recognized and minimized, resolution must improve, and substantial training will be necessary prior to widespread clinical use.

Artifacts↗

PubMed1998

Factor structure of the Wisconsin Card Sorting Test: dimensions of deficit in schizophrenia.

The aim of this study was to explore the factorial structure of the Wisconsin Card Sorting Test (WCST) and to identify the dimensions of deficit in schizophrenia. WCST scores in patients with schizophrenia and schizophrenia-related psychosis (n = 292), 1st degree relatives of schizophrenic patients (n = 91), and normal controls (n = 141) were subjected to a principal factor analysis followed by orthogonal rotation. This led to 3 factors, perseveration, failure to maintain set, and idiosyncratic sorting. The detected factor structure was found to be invariant across the schizophrenic and control subsamples. Moreover, it replicated previous findings from 2 smaller samples. Only perseverations and, to a lesser degree, idiosyncratic sorting appeared to differentiate schizophrenic patients from comparisons. Only perseveration had good sensitivity and specificity, as well as the most robust significant correlations with estimates of IQ, attention, and other measures of executive functioning. Thus, perseveration appears to be the most diagnostically useful and characteristic WCST feature of schizophrenia.

Adult↗

PubMed2003

Root fracture detection on digital images: effect of the zoom function.

UNLABELLED: To assess the accuracy of root fracture detection at various levels of image magnification. METHODS: Extracted single-rooted human teeth (100 non-fractured and 101 fractured) were mounted singly in wax blocks and a charge-coupled device (CCD)-based digital Sidexis imaging system was used to take images using the paralleling technique. Image sizes 1 : 1, 2 : 1, and 1 : 2 were prepared for each tooth. All 603 images were examined randomly and interpreted by an experienced radiologist unaware of which images were of fractured roots. The degree of agreement between image interpretation and the actual condition was estimated using a kappa statistic. A modified goodness-of-fit chi2-test was used to assess the significance of the difference between the three image sizes. The sensitivity, specificity, predictive value, and likelihood ratio were used to evaluate the accuracy of root fracture detection at each level of magnification. The degree of agreement between pairs of viewing conditions was also calculated using a kappa statistic. RESULTS: There was substantial agreement between image interpretation and the actual condition for both the 1 : 1 and 1 : 2 image sizes but only moderate agreement for the 2 : 1 size. The kappa values (and 95% CIs) were 0.65 (0.51-0.79), 0.63 (0.49-0.77), and 0.58 (0.44-0.72), respectively. The differences were not statistically significant (P-value = 0.79). The sensitivity (95% CI) of the image magnification ranged between 79.0% (70.0-87.5%) and 81.0% (72.2-87.5%). The 1 : 1 image size gave the highest specificity of 86.1% (95% CI: 78.1-91.6%). The positive predictive values (95% CI) of the 1 : 1, 1 : 2, and 2 : 1 images sizes were 84.9% (76.3-90.8%), 81.8% (73.1-88.2%), and 77.9% (69.0-84.8%), respectively. The negative predictive values (95% CI) were 80.6% (72.1-86.9%), 81.4% (73.8-88.9%), and 80.4% (71.4-87.1%) for the 1 : 1, 1 : 2, and 2 : 1 image sizes, respectively. The likelihood ratios of the positive test (95% CI) were 5.70 (3.47-9.36), 4.55 (3.00-6.98), and 3.56 (2.45-5,16) for the 1 : 1, 1 : 2, and 2 : 1 image sizes, respectively. The likelihood ratios of the negative test (95% CI) were 0.24 (0.17-0.36), 0.23 (0.15-0.35), and 0.25 (0.16-0.37) for the 1 : 1, 1 : 2, and 2 : 1 image sizes, respectively. The reliability between pairs of viewing conditions was substantial. The kappa statistics (95% CI) was 0.80 (0.72-0.88), 0.73 (0.64-0.83), and 0.77 (0.68-0.86), respectively. CONCLUSION: In this in vitro study, the three digital magnifications used did not affect the detection of root fractures.

Humans↗

PubMed1999

Major genetic effects on airway-parenchymal dysanapsis of the lung: the Humboldt family study.

We examined familial resemblance and performed segregation analysis for the maximal expiratory flow rate at 50% of vital capacity (Vmax50) and the ratio of Vmax50 to forced vital capacity (FVC), based on data from 309 nuclear families with 1,045 individuals in the town of Humboldt, Saskatchewan, in 1993. Vmax50 is considered as an index of airway function and Vmax50/FVC is considered as an index of airway-parenchymal dysanapsis. Both Vmax50 and Vmax50/FVC were preadjusted for host characteristics (age, height, and weight), environmental factors, and history of respiratory symptoms and diseases in four separate groups (mothers, fathers, daughters, and sons). Both Vmax50 and Vmax50/FVC showed low father-mother correlations and significant parent-offspring and sibling-sibling correlations. Segregation analysis indicated that for residual Vmax50, the model of no-parent-offspring transmission with possible heterogeneity between two generations fitted the data as well as did the general model with arbitrary transmission probabilities. The Mendelian hypothesis for Vmax50 was rejected, which was consistent with our previous findings for other indexes of airway function. For residual Vmax50/FVC, however, a single locus explained all the familial resemblance and both no-parent-offspring-transmission hypotheses [tau(AA) = tau(AB) = tau(BB) = qA and tau(AA) = tau(AB) = tau(BB)] were rejected. The study provides evidence for a single locus influencing airway-parenchymal dysanapsis.

Consanguinity↗

PubMed2002

Looking at the relationship between hemoglobin concentration and prevalent mobility difficulty in older women. Should the criteria currently used to define anemia in older people be reevaluated?

OBJECTIVES: The World Health Organization (WHO) and other currently used criteria for defining anemia in older women are mainly based on statistical distribution considerations. To explore their clinical appropriateness, we evaluated the relationship between hemoglobin (Hb) concentration, prevalent mobility difficulty, and the Summary Performance Score (SPS). DESIGN: Cross-sectional study. SETTING: Two population-based studies, the Women's Health and Aging Studies I and II, Baltimore, Maryland. PARTICIPANTS: Six hundred thirty-three community-dwelling women aged 70 to 80 with Hb levels obtained within 90 days from baseline assessment. MEASUREMENTS: Mobility difficulty (self-reported difficulty walking one-quarter of a mile or climbing 10 steps (primary outcome)). SPS, a performance-based summary measure of lower extremity function that combines the results of walking, chair stands, and balance tests (secondary outcome). RESULTS: Mobility difficulty prevalence was not constant within the WHO "normal" Hb range (12.0-16.0 g/dL). For example, a Hb of 13.5 g/dL was associated with a significantly lower mobility difficulty prevalence than a Hb of 12.0 g/dL (OR=0.68, 95% CI=0.47-0.93), even after adjustment for chronic diseases and other relevant health indicators. A consistent trend of improvement in performance-based scores with increasing Hb categories less than 12.0 g/dL, 12.0 to 13.0g/dL, and 13.0-14.0 g/dL was observed. CONCLUSION: Our findings raise two hypotheses: (1) Hb currently perceived as "mildly-low" and even "low-normal" might have an independent, adverse effect on mobility function, and (2) Hb of 12.0 g/dL might be a suboptimal criterion for defining anemia in older women. Formal testing of these hypotheses might prove relevant for anemia- and mobility disability-related clinical decision-making.

Aged↗

PubMed2002

The impact of a family empowerment intervention on juvenile offender heavy drinking: a latent growth model analysis.

We report the results of a growth model analysis of the impact of a Family Empowerment Intervention (FEI) on the heavy drinking over a 36-month follow-up period among youths processed at the Hillsborough County Juvenile Assessment Center. Families involved in the project were randomly assigned to either receive an Extended Services Intervention (ESI) or the FEI. Families in the ESI group received monthly phone contacts and, if indicated, referral information; FEI families received three one-hour, home-based meetings per week for approximately 10 weeks from a clinician-trained paraprofessional. By seeking to improve family functioning by empowering parents, it was hypothesized that target youths' behavior and psychosocial functioning would improve. Although the difference between FEI and ESI was not significant, the reported frequency of getting very high or drunk on alcohol declined more over time for FEI completers than FEI noncompleters. The results provide support for the impact of the FEI services.

Adolescent↗

PubMed1998

Estimating the parameters in the Cox model when covariate variables are measured with error.

The Cox proportional hazards model is commonly used to model survival data as a function of covariates. Because of the measuring mechanism or the nature of the environment, covariates are often measured with error and are not directly observable. A naive approach is to use the observed values of the covariates in the Cox model, which usually produces biased estimates of the true association of interest. An alternative strategy is to take into account the error in measurement, which may be carried out for the Cox model in a number of ways. We examine several such approaches and compare and contrast them through several simulation studies. We introduce a likelihood-based approach, which we refer to as the semiparametric method, and show that this method is an appealing alternative. The methods are applied to analyze the relationship between survival and CD4 count in patients with AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed2000

A new method for characterizing replacement rate variation in molecular sequences. Application of the Fourier and wavelet models to Drosophila and mammalian proteins.

We propose models for describing replacement rate variation in genes and proteins, in which the profile of relative replacement rates along the length of a given sequence is defined as a function of the site number. We consider here two types of functions, one derived from the cosine Fourier series, and the other from discrete wavelet transforms. The number of parameters used for characterizing the substitution rates along the sequences can be flexibly changed and in their most parameter-rich versions, both Fourier and wavelet models become equivalent to the unrestricted-rates model, in which each site of a sequence alignment evolves at a unique rate. When applied to a few real data sets, the new models appeared to fit data better than the discrete gamma model when compared with the Akaike information criterion and the likelihood-ratio test, although the parametric bootstrap version of the Cox test performed for one of the data sets indicated that the difference in likelihoods between the two models is not significant. The new models are applicable to testing biological hypotheses such as the statistical identity of rate variation profiles among homologous protein families. These models are also useful for determining regions in genes and proteins that evolve significantly faster or slower than the sequence average. We illustrate the application of the new method by analyzing human immunoglobulin and Drosophilid alcohol dehydrogenase sequences.

Alcohol Dehydrogenase↗

PubMed2001

Simultaneous modelling of operative mortality and long-term survival after coronary artery bypass surgery.

Typical analyses of lifetime data treat the time to death or failure as the response variable and use a variety of modelling strategies such as proportional hazards or fully parametric, to investigate the relationship between the response and covariates. In certain circumstances it may be more natural to view the distribution of the response variable as consisting of two or more parts since the survival curve appears segmented. This article addresses such a scenario and we propose a model for simultaneously investigating the effects of covariates over the two segments. The model is an analogue of that proposed by Lambert for zero-inflated Poisson regression. The application is central to the model development and is concerned with survival after coronary artery bypass surgery. Here operative mortality, defined as death within 30 days after surgery, and long-term mortality, are viewed as distinct outcomes. For the application considered, the survivor function displays much steeper descent during the first 30 days after surgery, that is, for operative mortality, than after this period. An investigation of the effects of covariates on operative and long-term mortality after coronary artery bypass surgery illustrates the usefulness of the proposed model.

Age Factors↗