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PubMed2007

A flexible model for multivariate interval-censored survival times with complex correlation structure.

We focus on the analysis of multivariate survival times with highly structured interdependency and subject to interval censoring. Such data are common in developmental genetics and genetic epidemiology. We propose a flexible mixed probit model that deals naturally with complex but uninformative censoring. The recorded ages of onset are treated as possibly censored ordinal outcomes with the interval censoring mechanism seen as arising from a coarsened measurement of a continuous variable observed as falling between subject-specific thresholds. This bypasses the requirement for the failure times to be observed as falling into non-overlapping intervals. The assumption of a normal age-of-onset distribution of the standard probit model is relaxed by embedding within it a multivariate Box-Cox transformation whose parameters are jointly estimated with the other parameters of the model. Complex decompositions of the underlying multivariate normal covariance matrix of the transformed ages of onset become possible. The new methodology is here applied to a multivariate study of the ages of first use of tobacco and first consumption of alcohol without parental permission in twins. The proposed model allows estimation of the genetic and environmental effects that are shared by both of these risk behaviours as well as those that are specific.

Adolescent↗

PubMed2000

Effects of dietary restriction and antioxidants on presbyacusis.

OBJECTIVES/HYPOTHESIS: The premise of this study is that the membrane hypothesis of aging, also known as the mitochondrial clock theory of aging, is the basis for presbyacusis. Furthermore, it is proposed that treatment with antioxidants or dietary restriction can attenuate age-related hearing loss. Many studies have demonstrated a reduction in blood flow to specific tissues, including the cochlea, with aging. Hypoperfusion leads to the formation of reactive oxygen metabolites (ROM). ROM are highly toxic molecules that directly affect tissues including inner ear structures. In addition, ROM can damage mitochondrial DNA (mtDNA), resulting in the production of specific mtDNA deletions (mtDNA del4977 [human] or mtDNA del4834 [rat]; also known as the common aging deletion]. Previous corroborating data suggest that the common aging deletion mtDNA4834 may be associated not only with aging but also with presbyacusis, thus further strengthening the basis of the current studies. In this study, experiments provide compelling evidence that long-term treatment with compounds that block or scavenge reactive oxygen metabolites attenuate age-related hearing loss and reduce the impact of associated deleterious changes at the molecular level. STUDY DESIGN: Prospective randomized study. METHODS: One hundred thirty rats were randomly assigned to one of six groups with appropriate controls. Animals were divided into the following treatment arms: group 1, 30% caloric restriction; group 2, vitamin E oversupplementation; group 3, vitamin C over-supplementation; group 4, melatonin treatment; group 5, lazaroid treatment; and group 6, placebo. In addition, 10 animals were used to determine the appropriate caloric restriction. All subjects underwent baseline and every-3-month testing until their health failed (range, 18-28 mo; average, 25 mo). This testing included auditory sensitivity studies using auditory brainstem response (ABR) testing, as well as tissue analysis for mtDNA deletions using molecular biological techniques. At the conclusion of the study, animals underwent a final ABR test and were tested for mtDNA deletions in brain and inner ear tissues, and the opposite ear was used for histological analysis. RESULTS: Results indicated that the 30%-caloric-restricted group maintained the most acute auditory sensitivities, the lowest quantity of mtDNA deletions, and the least amount of outer hair cell loss. The antioxidant-treated subjects had improved auditory sensitivities, and a trend for fewer mtDNA deletions was observed compared with the placebo subjects. The placebo subjects had the poorest auditory sensitivity, the most mtDNA deletions, and the greatest degree of outer hair cell loss. CONCLUSIONS: Intervention designed to reduce reactive oxygen metabolite damage appears to protect against age-related hearing loss specifically and aging in general. This is reflected by an overall reduction in mtDNA deletions. These data also suggest that the common aging deletion appears to be associated with presbyacusis, as demonstrated by an increased frequency of the mtDNA del4834 in the cochleae with the most significant hearing loss. Nutritional and pharmacological strategies may very well provide rational treatment options that would limit the age-associated increase in ROM generation, reduce mtDNA damage, and reduce the degree of hearing loss as the organism advances in age.

Animals↗

PubMed2006

Accurate haplotype inference for multiple linked single-nucleotide polymorphisms using sibship data.

Sibships are commonly used in genetic dissection of complex diseases, particularly for late-onset diseases. Haplotype-based association studies have been advocated as powerful tools for fine mapping and positional cloning of complex disease genes. Existing methods for haplotype inference using data from relatives were originally developed for pedigree data. In this study, we proposed a new statistical method for haplotype inference for multiple tightly linked single-nucleotide polymorphisms (SNPs), which is tailored for extensively accumulated sibship data. This new method was implemented via an expectation-maximization (EM) algorithm without the usual assumption of linkage equilibrium among markers. Our EM algorithm does not incur extra computational burden for haplotype inference using sibship data when compared with using unrelated parental data. Furthermore, its computational efficiency is not affected by increasing sibship size. We examined the robustness and statistical performance of our new method in simulated data created from an empirical haplotype data set of human growth hormone gene 1. The utility of our method was illustrated with an application to the analyses of haplotypes of three candidate genes for osteoporosis.

Algorithms↗

PubMed1999

Statewide system of electronic notifiable disease reporting from clinical laboratories: comparing automated reporting with conventional methods.

CONTEXT: Notifiable disease surveillance is essential to rapidly identify and respond to outbreaks so that further illness can be prevented. Automating reports from clinical laboratories has been proposed to reduce underreporting and delays. OBJECTIVE: To compare the timeliness and completeness of a prototypal electronic reporting system with that of conventional laboratory reporting. DESIGN: Laboratory-based reports for 5 conditions received at a state health department between July 1 and December 31, 1998, were reviewed. Completeness of coverage for each reporting system was estimated using capture-recapture methods. SETTING: Three statewide private clinical laboratories in Hawaii. MAIN OUTCOME MEASURES: The number and date of reports received, by reporting system, laboratory, and pathogen; completeness of data fields. RESULTS: A total of 357 unique reports of illness were identified; 201 (56%) were received solely through the automated electronic system, 32 (9%) through the conventional system only, and 124 (35%) through both. Thus, electronic reporting resulted in a 2.3-fold (95% confidence interval [CI], 2.0-2.6) increase in reports. Electronic reports arrived an average of 3.8 (95% CI, 2.6-5.0) days earlier than conventional reports. Of 21 data fields common to paper and electronic formats, electronic reports were significantly more likely to be complete for 12 and for 1 field with the conventional system. The estimated completeness of coverage for electronic reporting was 80% (95% CI, 75%-85%) [corrected] compared with 38% (95% CI, 36%-41%) [corrected] for the conventional system. CONCLUSIONS: In this evaluation, electronic reporting more than doubled the total number of laboratory-based reports received. On average, the electronic reports were more timely and more complete, suggesting that electronic reporting may ultimately facilitate more rapid and comprehensive institution of disease control measures.

Clinical Laboratory Information Systems↗

PubMed2000

Telepathology: a diagnostic tool for the millennium?

Many developments in science have their origins in science fiction and telepathology is no exception. The concept was first illustrated in 1924 in the magazine 'Radio News'. It was not until 1980, however, that the first working telepathology system was demonstrated. Although the system was shown to work, it required special hardware, dedicated software and special microwave transmission links to be installed. Little interest was shown worldwide because of the very high cost and the inability of many people to replicate such a system. Ten years later, the personal computer (PC) was able to provide more than adequate performance at low cost for both image display quality and speed, and the development of video technology had resulted in high quality images being produced by television cameras that were now easily affordable. Microscopes were also relatively cheaper. Thus, by 1993 or 1994, all the hardware necessary to produce a telepathology system was available at reasonable cost. Telepathology can now be used for remote primary diagnosis, remote referral to a specialist pathologist, remote teaching, remote presentation of post-mortem or microscopic findings, quality assurance image circulation and feedback, and consensus diagnosis for pathological review in clinical trials. There are two residual problems. The first concerns the speed of data transmission, commonly referred to as the bandwidth. The second is that the software provided by most of the manufacturers and suppliers of these systems is not entirely suitable to the task and the systems are not interoperable. It is clear that the approach of the manufacturers is at present unlikely to produce telepathology systems which pathologists feel comfortable in using. A somewhat different approach is illustrated by the accompanying article in this issue from the Berlin group, where a relatively simple Java-based applet and the Internet are used to allow single or multiple users to view slides on a robotic microscope. This could form the basis for a truly useful system, but still needs modification for some applications.

Clinical Trials as Topic↗

PubMed1998

Body image and dieting behaviors among elite figure skaters.

OBJECTIVE: This study explored links among body image, dieting behavior, and nutritional status among 40 nationally ranked junior figure skaters. METHOD: Questionnaires were provided to 40 junior skaters (range 12.9-22.9 years) during a skaters' camp. Food intakes were recorded over 4 consecutive days and blood samples were drawn. Nutritional status was assessed using food intake records and selected biomarker data. RESULTS: Data suggested that these athletes dieted despite relative satisfaction with body image. Although biochemical measures of nutritional status were all within normal range, inadequate energy intakes and delayed menarche (in women) were widespread in this athlete sample. DISCUSSION: Data dispute common theories of dieting being linked to dissatisfaction with body image. The article also cautions against overreliance on biochemical assessment as a marker of nutritional inadequacy.

Adolescent↗

PubMed1995

Modeling epidemiologic studies of occupational cohorts for the quantitative assessment of carcinogenic hazards.

Epidemiologic studies of occupational cohorts have played a major role in the quantitative assessment of risks associated with several carcinogenic hazards and are likely to play an increasingly important role in this area. Relatively little attention has been given in either the epidemiologic or the risk assessment literature to the development of appropriate methods for modeling epidemiologic data for quantitative risk assessment (QRA). The purpose of this paper is to review currently available methods for modeling epidemiologic data for risk assessment. The focus of this paper is on methods for use with retrospective cohort mortality studies of occupational groups for estimating cancer risk, since these are the data most commonly used when epidemiologic information is used for QRA. Both empirical (e.g., Poisson regression and Cox proportionate hazards model) and biologic (e.g., two-stage models) models are considered. Analyses of a study of lung cancer among workers exposed to cadmium are used to illustrate these modeling methods. Based on this example it is demonstrated that the selection of a particular model may have a large influence on the resulting estimates of risk.

Cadmium↗

PubMed2001

Maxillary canine-first premolar transposition in two Native American skeletal samples from New Mexico.

Tooth transposition is a rare anomaly in which the position of two adjacent teeth in the dental arcade is reversed. Maxillary canine and first premolar transposition (Mx.C.P1 transposition) is most commonly observed. Data from Native Americans samples are lacking. The purpose of this study was: 1) to document the occurrence of Mx.C.P1 transposition, and 2) to generate information on the prevalence of this transposition type among world populations. Eleven cases (M = 5, F = 4, ? = 2) of Mx.C.P1 transposition were identified in skeletal samples from Pecos Pueblo (n = 500) and Sambrito Village (n = 10), both in northern New Mexico. Nine cases were unilateral, 6 affecting the right side and 3 affecting the left side. The remaining 2 cases were bilateral. The prevalence rate of Mx.C.P1 transposition in African and Native American samples, including Pecos Pueblo (1.8%), is higher than in samples from Scotland, Sweden, Saudi Arabia, and India. Mx.C.P1 transposition frequencies vary between geographically distinct populations, although sample composition may be a factor contributing to sample variation.

Anthropology, Physical↗

PubMed1979

Size and morphology of the permanent dentition in prehistoric Ohio Valley Amerindians.

Metric and morphological characterizations of the permanent teeth from a total of 155 prehistoric Amerindians are presented. The individuals represent samples from three Ohio Valley burial complexes (considered together as the Late Diffuse group): Glacial Kame, Adena and Ohio Hopewell. Metric data include common measures of central tendency and dispersion. From these measures estimates and analyses of the magnitude of sexual dimorphism and relative variability are presented as well as analyses of the patterns of these estimates. Forty morphological characters are also tabulated. The results indicate a number of provisional hypotheses: the generally larger tooth size of the Late Archaic Indian Knoll when compared to the Late Diffuse groups is consistent with the hypothesis of mitigated selective pressures in more technologically advanced groups; although tooth size is smaller in the Late Diffuse groups, dental morphology is as complex, or more so when compared to the Indian Knoll group. Since morphology and size do not covary exactly the biocultural forces resulting in smaller tooth size do not seem to act as strongly on dental morphology; odontological differences within the Late Diffuse arise primarily between the Glacial Kame-Adena and the Ohio Hopewell. These differences correspond to major biocultural changes in this area; although provisional hypotheses concerning odontological variability are erected, hypotheses concerning evolutionary trends must await the discovery of evolving lineages within these groups; similarities are noted among all compared groups including the pattern and magnitude of sexual dimorphism and relative variability. These parameters may be similar for all eastern Amerindians during this period; finally, the morphology of the deciduous dentition, which generally predicts that of the permanent teeth, is found to be less complex than the permanent teeth. This may be the result of a selective disadvantage for the individuals in the deciduous dentition sample which is reflected in the dentition.

Cuspid↗

PubMed1992

Paternal uniparental disomy of chromosome 15 in a child with Angelman syndrome.

Angelman and Prader-Willi syndromes are clinically distinct neurobehavioral disorders most commonly resulting from large deletions of chromosome 15q11-q13. The deletions arise differentially during maternal or paternal gametogenesis, respectively. A subgroup of patients with either syndrome have no apparent deletion, and because many such patients with Prader-Willi syndrome display inheritance of two copies of chromosome 15 from the mother only (uniparental disomy; UPD), we suggested that paternal UPD might be found in patients with Angelman syndrome. We report here clinical, cytogenetic, and molecular evidence on the 1 patient with paternal UPD for chromosome 15 who was found in our study population. This represents, to our knowledge, the first patient with paternal UPD to be studied with DNA probes from the chromosome 15q11-q13 critical region. In contrast to our findings for patients with Prader-Willi syndrome, in which maternal UPD was common, our data demonstrate that paternal UPD is infrequent in patients with Angelman syndrome.

Angelman Syndrome↗

PubMed1995

Timing, mode, and predictors of death after direct angioplasty for acute myocardial infarction.

The timing and mechanisms of early (30 day) mortality in 330 consecutive patients treated with direct angioplasty less than 12 hr after onset of myocardial infarction without antecedent thrombolysis were studied. There were 38 deaths (11.5% of pts), with a majority being due to cardiogenic shock (76%). Other causes included acute closure (11%), death after emergency bypass surgery (5%), ventricular arrhythmias (5%), and respiratory failure (3%). No deaths from stroke or cardiac rupture were seen, in contrast to trials of thrombolytic agents. Most deaths were seen early, with 47% occurring within 1 day, 35% from days 2-7, and 18% from days 8-30. Death from cardiogenic shock was the most common cause of death throughout this period: 83% of deaths in days 0-3, 88% of deaths in days 4-6, and 43% of deaths in days 8-30. Significant predictors of early death included older age (P < .0001), multi-vessel disease (P < .05), direct angioplasty failure (P < .05), reduced ejection fraction (P < .0001), and anterior myocardial infarction (P < .0005). Gender, prior myocardial infarction, and prior bypass surgery did not affect mortality. Cardiogenic shock is the most common cause of early death after direct angioplasty for myocardial infarction. Patients with one or more risk factors for early death may benefit from additional myocardial salvage or revascularization efforts in the early post-infarct period. Certain causes of death after direct angioplasty (cardiac, rupture, stroke) appear to be less common than data reported for lytic therapy for myocardial infarction.

Adult↗

PubMed1980

Receptive field properties of simple and complex striate neurons in Siamese cats.

Responses of striate cortical cells in Midwestern Siamese cats to moving slits and stationary flashed spots were recorded and compared to similar data in common cat controls obtained under identical experimental conditions. Over 90% of the neurons sampled had receptive fields within 10 degrees of the area centralis. The proportion of binocularly excited cells in Siamese striate cortex was less than that found in the control cats, but more than has previously been reported, and was inversely related to the extent of convergent misalignment exhibited by each animal. Those striate neurons which could be driven by either eye had normal binocular receptive fields and demonstrated normal binocular interaction effects except facilitation. Receptive field dimensions (length, width, area) were significantly larger in Siamese than in common cats. For the simple cells, strabismic Siamese cats had larger receptive fields than orthophoric Siamese cats. Average spontaneous activity in Siamese cats was significantly higher than in the controls. However, similar encounter rates of simple, complex, and hypercomplex units were observed in both Siamese and common cats, and peak responses were not different. Velocity preference in complex Siamese units was shifted to slower velocities compared to common cat complex cells. A loss of direction selectivity was also revealed in the Siamese simple and complex neurons. Finally, sharpness of orientation tuning was dramatically reduced in Siamese complex cells, and this reduction was directly related to the extent of convergent squint exhibited by each animal. The results are discussed in terms of developmental anomalies and neurophysiological retinal abnormalities in Siamese cats.

Animals↗

PubMed1992

Chromosomal abnormalities in skin following total body or total lymphoid irradiation.

Patients undergoing bone marrow transplantation often receive total body or total lymphoid irradiation as part of the conditioning regimen prior to marrow infusion. The cytogenetic effects of this therapy on skin fibroblasts were studied. Fibroblast cultures from eight skin biopsies were harvested in early passages for G-banded chromosome analysis. Four biopsies were from three patients who had high-dose cyclophosphamide and total body radiotherapy; one was from within and one was from outside the radiation field of a patient who had high-dose cyclophosphamide and lymphoid radiotherapy, one was from a patient who had combination chemotherapy alone, and one was from a normal control. No abnormal mitoses were found in the control or the patient who had chemotherapy alone, and only two of 30 mitoses from skin outside the lymphoid radiotherapy field were abnormal. However, most cells (49-88%) from five biopsies within radiotherapy fields were abnormal. Typically, abnormal karyotypes were pseudodiploid and contained multiple balanced rearrangements, of which reciprocal translocations were most common. The data indicate that the radiotherapy used for bone marrow transplantation induces extensive, sustained chromosome abnormalities in vivo in skin fibroblasts.

Adolescent↗

PubMed1995

Genetic epidemiologic analysis of quantitative phenotypes using Gibbs sampling.

We analyzed two quantitative traits (Q1 and Q2) provided in the 'Common Disease' data set with the aim of detecting both genetic and environmental determinants. We used linear regression for screening measured variables, maximum likelihood segregation and linkage analyses for detecting and localizing unmeasured genes, and Gibbs sampling for joint segregation and linkage analyses with estimation of gene-environment interaction and polygenic effects. For both Q1 and Q2, we successfully detected the unmeasured codominant major gene (MG) that was tightly linked to candidate gene C2. We also detected all of the measured variables used in generating Q1 (age, Q3, candidate gene C5) and Q2 (EF). Although our final models differed slightly from the true data generation models, our multifaceted analytic approach was successful in characterizing the determinants of Q1 and Q2.

Alleles↗

PubMed2006

NMR of conotoxins: structural features and an analysis of chemical shifts of post-translationally modified amino acids.

Conotoxins are small conformationally constrained peptides found in the venom of marine snails of the genus Conus. They are usually cysteine rich and frequently contain a high degree of post-translational modifications such as C-terminal amidation, hydroxylation, carboxylation, bromination, epimerisation and glycosylation. Here we review the role of NMR in determining the three-dimensional structures of conotoxins and also provide a compilation and analysis of 1H and 13C chemical shifts of post-translationally modified amino acids and compare them with data from common amino acids. This analysis provides a reference source for chemical shifts of post-translationally modified amino acids.

Amino Acids↗

PubMed2002

Test-retest reliability estimation of functional MRI data.

Functional magnetic resonance imaging (fMRI) data are commonly used to construct activation maps for the human brain. It is important to quantify the reliability of such maps. We have developed statistical models to provide precise estimates for reliability from several runs of the same paradigm over time. Specifically, our method extends the premise of maximum likelihood (ML) developed by Genovese et al. (Magn Reson Med 1997;38:497-507) by incorporating spatial context into the estimation process. Experiments indicate that our methodology provides more conservative estimates of true positives compared to those obtained by Genovese et al. The reliability estimates can be used to obtain voxel-specific reliability measures for activated as well as inactivated regions in future experiments. We derive statistical methodology to determine optimal thresholds for region- and context-specific activations. Empirical guidelines are also provided on the number of repeat scans to acquire in order to arrive at accurate reliability estimates. We report the results from experiments involving a motor paradigm performed on a single subject several times over a period of 2 months.

Brain↗

PubMed2006

Uroselectivity in male dogs of silodosin (KMD-3213), a novel drug for the obstructive component of benign prostatic hyperplasia.

AIMS: Our main aim was to compare the prostatic selectivity of silodosin with that of other alpha(1)-adrenoceptor (AR) antagonists. METHODS: We examined uroselectivities in two sets of experiments namely, in vitro and in vivo functional studies using male dogs. In the in vitro study, after evaluating the inhibitory effects of silodosin on noradrenaline (NA)-induced contractions in the isolated prostate and isolated carotid artery using the Magnus method, we calculated prostatic selectivity. In the in vivo study, we examined the effects of drugs on the hypogastric nerve stimulation (HNS)-induced increase in intraurethral pressure (IUP) and on blood pressure. The uroselectivity of silodosin was compared with those of tamsulosin and naftopidil. RESULTS: In vitro, all drugs antagonized NA-induced contraction in both prostate and carotid artery. The prostatic selectivity of silodosin (79.4) was much higher than those of tamsulosin (1.78), naftopidil (0.55), BMY 7378 (0.115), and prazosin (0.01). In vivo, intravenously (i.v.) administered silodosin dose-dependently inhibited the HNS-induced increase in IUP with much less hypotensive effect than either tamsulosin or naftopidil, the uroselectivity (ED(15)/ID(50)) of silodosin (237) being significantly higher than those of tamsulosin (1.21) and naftopidil (2.65). CONCLUSIONS: Our results clearly demonstrate that silodosin is a potent and highly selective alpha(1A)-AR antagonist. A selective alpha(1A)-AR antagonist such as silodosin may have good potential as a less-hypotensive drug for the treatment of urinary dysfunction in benign prostatic hyperplasia patients.

Adrenergic alpha-1 Receptor Agonists↗

PubMed2004

Common interchange standards for proteomics data: Public availability of tools and schema.

The Proteomics Standards Initiative (PSI) aims to define community standards for data representation in proteomics and to facilitate data comparision, exchange and verification. To this end, a Level 1 Molecular Interaction XML data exchange format has been developed which has been accepted for publication and is freely available at the PSI website (http.//psidev.sf.net/). Several major protein interaction databases are already making data available in this format. A draft XML interchange format for mass spectrometry data has been written and is currently undergoing evaluation whilst work is ongoing to develop a proteomics data integration model, MIAPE.

Computational Biology↗