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L Hsu

Publications and source records attributed to L Hsu.

At least 73 records · Page 4Linked to original sources
PubMed2000

Effects of age at onset on the power of the affected sib pair and transmission/disequilibrium tests.

Information on the age of a patient at disease onset, an important feature of complex diseases, is often collected in studies designed to map the disease genes. Penetrance-model-free methods, requiring no specification of penetrance functions, have been used extensively for detecting linkage and association between marker and disease loci. In this paper, we conduct an analytical study to examine the effects of incorporation of age at onset information on the power of two commonly used penetrance-model-free methods, the affected sib-pair (ASP) and transmission/disequilibrium tests (TDT). Assuming a Cox model with a major gene effect for the age at onset, we quantify analytically how age at onset affects the identity by descent (IBD) probabilities, the mean IBD values, and the expected numbers of alleles transmitted from heterozygous parents to affected children under various genetic models. We show that the power of the mean IBD test and the TDT can be greatly affected by the ages at onset of affected siblings or children used in the study. Generally, the most powerful test for ASPs is that based on affected sib pairs both having early disease onset and for TDT analyses is that based on trios with early-onset children. Naively combining affected sib pairs with different ages at onset or parent-children trios with different ages at onset of affected children can result in reduced power for detecting linkage or association. These results may be used to guide collection and analysis of sib pairs or families for diseases with variable age at onset.

Adult↗
PubMed2000

Familial aggregation of dyslexia phenotypes.

There is evidence for genetic contributions to reading disability, but the phenotypic heterogeneity associated with the clinical diagnosis may make identification of the underlying genetic basis difficult. In order to elucidate distinct phenotypic features that may be contributing to the genotypic heterogeneity, we assessed the familial aggregation patterns of Verbal IQ and 24 phenotypic measures associated with dyslexia in 102 nuclear families ascertained through probands in grades 1 through 6 who met the criteria for this disorder. Correlations between relatives were computed for all diagnostic phenotypes, using a generalized estimating equation (GEE) approach. GEE is a recently developed semiparametric method for handling correlated data. The method is robust to model misspecification and flexible in adjusting for the subjects' characteristics and pedigree sizes as well as for the ascertainment process, while estimating the correlations between related subjects. The Nonword Memory (NWM) subtest of a prepublication version of the Comprehensive Test of Phonological Processing (CTOPP) and Phonemic Decoding Efficiency (PDE) subtest of a prepublication version of the Test of Word Reading Efficiency (TOWRE) showed correlation patterns in relatives that are strongly supportive of a genetic basis. The Wechsler Scale Digit Span, the Word Attack subtest of the Woodcock Reading Mastery Test--Revised, and the Spelling subtest of the Wide Range Achievement Test--Third Edition had slightly weaker evidence of a genetic basis. Five additional phenotypes (the Spelling subtest of the Wechsler Individual Achievement Test, the Accuracy, Rate, and Comprehension subtests of the Gray Oral Reading Test--Third Edition, and Rapid Automatized Naming of Letters and Numbers) gave suggestive evidence of such a pattern. The results cross-validate in that evidence for a pattern consistent with a genetic basis was obtained for two measures of phonological short-term memory (CTOPP Nonword Memory and WISCIII or WAIS-R Digit Span), for two measures of phonological decoding (WRMT-R Word Attack and TOWRE Phonemic Decoding Efficiency), and for two measures of spelling from dictation (WRAT-3 Spelling and, to a lesser extent, WIAT Spelling). These measures are thus good candidates for more sophisticated segregation analyses that can formulate models for incorporation into linkage analyses.

Adult↗
PubMed2000

Dependence estimation over a finite bivariate failure time region.

This article concerns nonparametric estimation of association between bivariate failure times. In the presence of independent right censoring, the support for failure time variates may be restricted and measures of dependence over a finite failure time region may be of particular interest. To this end, the reciprocal cross ratio function, weighted by the bivariate failure time density, is proposed as a summary measure of dependence over a failure time region. This 'relative risk' estimator is shown to be consistent and asymptotically normally distributed, with consistent bootstrap variance estimator. A finite-region version of Kendall's tau, which is suitable for censored failure time data, is also proposed, and corresponding asymptotic distribution theory is noted. The accuracy of these asymptotic approximations is studied in simulations and an illustration is provided.

Adolescent↗
PubMed1999

An efficient, robust and unified method for mapping complex traits (III): combined linkage/linkage-disequilibrium analysis.

Extending the method for linkage analysis [Zhao et al., 1998a: Am. J. Med. Genet. 77:366-383; 1998b: Am. J. Med. Genet. 79:49-61], this article describes a method for the linkage-disequilibrium analysis, and for combining linkage and linkage-disequilibrium analyses. As highly dense markers are increasingly used in genome scans, one or more markers are not only linked with the disease genes if they exist, but also likely in linkage-disequilibrium with those putative genes. Hence, linkage-disequilibrium analysis potentially offers additional information about positions of putative disease genes. Combining both linkage and linkage-disequilibrium signals, this approach is able to improve positional signals. As before, the proposed method is a model-based approach, but semiparametric via the estimating equation technique. Under the assumptions of penetrance and allele frequency, this method efficiently estimates recombination fractions for linkage analysis and odds ratios for linkage-disequilibrium analysis. As described in two previous papers, this method is relatively more robust than the lod score methods, since it requires weaker assumption than conditional independence. While the estimated recombination fractions are used for inference as part of linkage analysis, the estimated odds ratios are used for linkage-disequilibrium inference and combined linkage, and linkage-disequilibrium parameters can be used to test combined linkage/linkage-disequilibrium analysis. This approach has been implemented, named gSCAN, and its compiled version is available for trial on request via the web site (http:/lynx.fhcrc.org/qge). We applied this new approach to affected sib-pair data collected for the genome scan to localize type 1 diabetes genes. Under an assumed autosomal dominant gene model, the linkage analysis confirms an earlier suggestion of one major gene around D6S281. Interestingly, the linkage-disequilibrium analysis suggests several additional signals around D6S250, GATA30, D6S311, D6S441, D6S442, D6S415, D6S411, D6S305, and a290xh9. The linkage analysis, on the other hand, suggests a signal around D6S281, while providing supporting evidence for several other marker loci. However, the combined analysis did not provide strong support for any of the findings, implying that linkage and linkage-disequilibrium findings are not consistent.

Alleles↗
PubMed1999

Mapping alcoholism genes using linkage/linkage disequilibrium analysis.

Using a recently developed semiparametric method for combined linkage/linkage-disequilibrium analysis, we analyzed the Collaborative Study on the Genetics of Alcoholism data subset developed for Genetic Analysis Workshop 11 (GAW11). This semiparametric approach estimates recombination fractions for linkage, marker log odds ratios for linkage-disequilibrium, their product for combined linkage/linkage-disequilibrium, and corresponding z-scores. We used two outcomes: alcohol dependence and "alcoholism-free" and a genome-wide significance level of 4.1 (which corresponds to a genome-wide lod score of 3.6). For the alcohol dependence outcome, we observed significant linkage signals at D1S1588-D1S1631, D1S547, D2S399, D2S425, D4S2361, D7S1796, and D7S1824. We also found significant linkage-disequilibrium signals at D1S547 and D7S1795. For the "alcoholism-free" outcome, we found significant linkage signals at D4S2457, D41651 (both flank ADH3), D11S2359, and D16S47 and significant linkage-disequilibrium signals at D4S2361, FABP2, D11S2359, D19S431 and D19S47-D19S198-D19S601.

Alcoholism↗
PubMed1999

A genome-wide scan for a simulated data set using two newly developed methods.

A genome-wide scan of a simulated data set for fictitious disease genes was conducted using both semiparametric and nonparametric methods. The semiparametric model-based method, which tests for linkage/linkage disequilibrium separately and together, correctly identified all three underlying disease loci along with two false positives through the linkage analysis. However, the nonparametric model-free method which tests combined linkage/linkage disequilibrium, failed to yield any results due to the lack of linkage disequilibrium information in the data.

Chromosome Mapping↗
PubMed1999

Acute exercise enhances receptor-mediated endothelium-dependent vasodilation by receptor upregulation.

The effects of acute exercise on receptor-mediated endothelium-dependent vasodilation and its possible mechanisms were investigated in the presence of indomethacin. Male Wistar rats (16-20 weeks old) were divided into control and exercise groups. The exercise group ran on a drum exerciser until exhaustion, followed by immediate decapitation. Acetylcholine (ACh)- or clonidine (CLO)-induced vasodilating responses in thoracic aortae of the control and exercise groups were compared. Receptor-binding assays were performed to determine whether there were any upregulations of endothelial receptors after acute exercise. Our results indicated that acute exercise induced the following effects: (1) the dose-response curves of ACh and CLO shifted to the left; (2) the high-affinity M3 binding sites increased in number but not in affinity; (3) the alpha2 binding sites decreased in number but increased in affinity. We conclude that acute exercise enhances receptor-mediated vasodilation responses, at least in part, by regulating either endothelial receptor number or receptor affinity.

Acetylcholine↗
PubMed1999

In vitro synaptotrophic effects of Cerebrolysin in NT2N cells.

Recent studies have shown that Cerebrolysin can enhance synaptic function and ameliorate synaptodendritic alterations in animal models of neurodegeneration, suggesting a synaptotrophic effect. We hypothesize that Cerebrolysin might exert this effect, in part, by regulating the expression of amyloid precursor protein (APP). We studied the patterns of expression of synaptic proteins during differentiation of human teratocarcinoma cell line NTera 2 (NT2) in the presence or absence of Cerebrolysin. This study showed that the terminally differentiated neurons (NT2N) expressed a wide variety of synaptic markers and that expression of these synaptic-associated proteins coincided with the shift in expression from APP770/751 to APP695. Furthermore, APP immunoreactivity was colocalized with synaptophysin-immunoreactive neuritic varicosities in NT2N neurites, and Cerebrolysin treatment of NT2N cells resulted in an augmented and earlier expression of synaptic-associated proteins. This increased synaptic protein expression coincided with an increase in APP695 over APP770/751. These results support the possibility that synaptotrophic effects of Cerebrolysin might be mediated via regulation of APP expression.

Amino Acids↗
PubMed1999

On the assessment of statistical significance in disease-gene discovery.

One of the major challenges facing genome-scan studies to discover disease genes is the assessment of the genomewide significance. The assessment becomes particularly challenging if the scan involves a large number of markers collected from a relatively small number of meioses. Typically, this assessment has two objectives: to assess genomewide significance under the null hypothesis of no linkage and to evaluate true-positive and false-positive prediction error rates under alternative hypotheses. The distinction between these goals allows one to formulate the problem in the well-established paradigm of statistical hypothesis testing. Within this paradigm, we evaluate the traditional criterion of LOD score 3.0 and a recent suggestion of LOD score 3.6, using the Monte Carlo simulation method. The Monte Carlo experiments show that the type I error varies with the chromosome length, with the number of markers, and also with sample sizes. For a typical setup with 50 informative meioses on 50 markers uniformly distributed on a chromosome of average length (i.e., 150 cM), the use of LOD score 3.0 entails an estimated chromosomewide type I error rate of.00574, leading to a genomewide significance level >.05. In contrast, the corresponding type I error for LOD score 3.6 is.00191, giving a genomewide significance level of slightly <.05. However, with a larger sample size and a shorter chromosome, a LOD score between 3.0 and 3.6 may be preferred, on the basis of proximity to the targeted type I error. In terms of reliability, these two LOD-score criteria appear not to have appreciable differences. These simulation experiments also identified factors that influence power and reliability, shedding light on the design of genome-scan studies.

Chromosome Mapping↗
PubMed1999

Integrated designs for gene discovery and characterization.

Recent advances, including near completion of the human genome map, ever improving high-throughput technologies, and successes in discovering chronic disease-related genes, have stimulated the further development of genetic epidemiology. The primary mission of genetic epidemiology is to discover and characterize genes, whether independent of or interactive with environmental factors, that cause human diseases. To accomplish such a mission, genetic epidemiology needs to integrate both genetic and epidemiologic approaches. One of the challenges facing such an integrated approach is the identification of study designs that are efficient for both gene discovery and characterization. Because designs for gene discovery alone and designs for gene characterization alone have been elaborated in the other two panels, the focus of this paper is to describe those designs that may be useful for discovery and characterization jointly, including case-family and case-control-family designs. Examples of integrated designs are described, and studies of breast cancer conducted at the Fred Hutchinson Cancer Research Center are used for illustration. Finally, related analytic issues are also discussed.

Breast Neoplasms↗
PubMed1999

Intraoperative MR imaging guidance for intracranial neurosurgery: experience with the first 200 cases.

PURPOSE: To review preliminary experience with an open-bore magnetic resonance (MR) imaging system for guidance in intracranial surgical procedures. MATERIALS AND METHODS: A vertically oriented, open-configuration 0.5-T MR imager was housed in a sterile procedure room. Receive and transmit surface coils were wrapped around the patient's head, and images were displayed on monitors mounted in the gap of the magnet and visible to surgeons. During 2 years, 200 intracranial procedures were performed. RESULTS: There were 111 craniotomies, 68 biopsies, 12 intracranial cyst evaluations, four subdural drainages, and five transsphenoidal pituitary resections performed with the intraoperative MR unit. In each case, the intraoperative MR system yielded satisfactory results by allowing the radiologist to guide surgeons toward lesions and to assist in treatment. In two patients, hyperacute hemorrhage was noted and removed. The duration of the procedure and the complication rate were similar to those of conventional surgery. CONCLUSION: Intraoperative MR imaging was successfully implemented for a variety of intracranial procedures and provided continuous visual feedback, which can be helpful in all stages of neurosurgical intervention without affecting the duration of the procedure or the incidence of complications. This system has potential advantages over conventional frame-based and frameless stereotactic procedures with respect to the safety and effectiveness of neurosurgical interventions.

Adolescent↗
PubMed1999

Virtual laryngoscopy.

Virtual endoscopy enables computer-generated 3-dimensional visualization of a cavity by reconstructing 2-dimensional computed tomographic or magnetic resonance data. The technique has been used experimentally to study the colon, bronchi, ears, and other structures. Here, virtual laryngoscopies were created from the cross-sectional image data of 3 patients. The cases represented a normal airway, a squamous cell carcinoma of the glottic fold, and a posterior glottic stenosis. These reconstructions included extraluminal anatomy that is not typical of current virtual endoscopic techniques. The 2-dimensional computed tomographic and magnetic resonance images of the patients underwent post-processing for 3-dimensional reconstruction. The resulting models were imported into an experimental virtual endoscopy program for 1) airway lumen generation and 2) interactive viewing. Though they could not be used for biopsy, the virtual laryngoscopies provided, in a noninvasive fashion, good simulation of endoscopy. Virtual endoscopy also gave the added benefits of the ability to assess the transmural extent of disease and view the airway distal to areas of luminal compromise. This technology may well provide clinical benefit in preoperative planning, staging, and intraprocedural guidance for head and neck disease and merits further study.

Adult↗
PubMed1998

An efficient, robust, and unified method for mapping complex traits (II): multipoint linkage analysis.

Extending the method for two-point linkage analysis [Zhao et al., 1998: Am J Med Genet 77:366-383], this paper introduces a semiparametric method for multipoint linkage analysis, expected to gain efficiency by using multiple markers simultaneously. Overcoming the longstanding statistical and computational challenge to the parametric approaches (or lod score methods) for multipoint linkage analysis, this semiparametric approach, based on the estimating equation technique, yields statistically efficient and yet robust estimates and enjoys the computational efficiency in processing multiple markers from large pedigrees. Its computational burden increases linearly with the sizes of pedigrees and with the number of marker loci. To illustrate this semiparametric method, we apply it to marker data gathered for the Breast Cancer Consortium. The result supports the earlier finding of the positive linkage with BRCA1 and has also shown that the multipoint linkage analysis has an improved power. In addition, we have applied this method to analyze genome scanning data that have been used to localize genes responsible for type 1 diabetes. In support of the earlier findings, the genome scanning detects the linkage signals on chromosome 6 but does not support the earlier suggestions of two major genes in that genome segment. Through sensitivity analysis, it appears that the results are robust to misspecification of penetrance and allele frequency.

Automation↗
PubMed1998

Impact of socioeconomic status on survival with AIDS.

Prior studies of the association between socioeconomic status and length of survival among persons infected with the human immunodeficiency virus (HIV) have produced conflicting results. To investigate this issue further, the authors examined data on 18,167 San Francisco, California, residents aged 13 years or older who were diagnosed with acquired immunodeficiency syndrome (AIDS) between January 1, 1985, and December 31, 1995. Three validated US census-based measures of socioeconomic status were used: poverty, predominantly working class neighborhood, and low educational level. Median length of survival was found to be similar for persons living in neighborhoods characterized by poverty (22 months) and those in higher income neighborhoods (23 months), for persons living in predominantly working class neighborhoods (22 months) and those in predominantly professional/managerial neighborhoods (23 months), and for persons living in neighborhoods characterized by low educational level (23 months) and those in neighborhoods characterized by higher educational level (23 months). After adjustment for sex, age, ethnicity, AIDS risk group, site of AIDS diagnosis, time period of AIDS diagnosis, and AIDS-indicator illness, no association was found between survival and living in a neighborhood characterized by poverty (relative hazard (RH)=1.03, 95% confidence interval (CI) 0.97-1.08), between survival and working class occupations (RH=1.03, 95% CI 0.98-1.08), or between survival and low educational level (RH=0.96, 95% CI 0.90-1.01). The lack of an association between socioeconomic status and length of survival with AIDS may be due to the high mortality from AIDS in the era prior to highly effective antiretroviral therapy or to similar levels of access to care in San Francisco.

AIDS-Related Opportunistic Infections↗
PubMed1998

Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography.

BACKGROUND: Blood transfusions prevent recurrent stroke in children with sickle cell anemia, but the value of transfusions in preventing a first stroke is unknown. We used transcranial Doppler ultrasonography to identify children with sickle cell anemia who were at high risk for stroke and then randomly assigned them to receive standard care or transfusions to prevent a first stroke. METHODS: To enter the study, children with sickle cell anemia and no history of stroke had to have undergone two transcranial Doppler studies that showed that the time-averaged mean blood-flow velocity in the internal carotid or middle cerebral artery was 200 cm per second or higher. The patients were randomly assigned to receive standard care or transfusions to reduce the hemoglobin S concentration to less than 30 percent of the total hemoglobin concentration. The incidence of stroke (cerebral infarction or intracranial hemorrhage) was compared between the two groups. RESULTS: A total of 130 children (mean [+/-SD] age, 8.3+/-3.3 years) were enrolled; 63 were randomly assigned to receive transfusions and 67 to receive standard care. At base line, the transfusion group had a slightly lower mean hemoglobin concentration (7.2 vs. 7.6 g per deciliter, P=0.001) and hematocrit (20.4 vs. 21.7 percent, P=0.002). Ten patients dropped out of the transfusion group, and two patients crossed over from the standard-care group to the transfusion group. There were 10 cerebral infarctions and 1 intracerebral hematoma in the standard-care group, as compared with 1 infarction in the transfusion group -- a 92 percent difference in the risk of stroke (P<0.001). This result led to the early termination of the trial. CONCLUSIONS: Transfusion greatly reduces the risk of a first stroke in children with sickle cell anemia who have abnormal results on transcranial Doppler ultrasonography.

Adolescent↗
PubMed1998

Efficient, robust, and unified method for mapping complex traits (I): two-point linkage analysis.

The completion of a preliminary human genome map and development of molecular methods have enabled researchers to assay a large number of polymorphic markers that are evenly spaced along the entire human genome. Among many applications, marker data are valuable for mapping complex traits through linkage or linkage-disequilibrium analysis, the former of which is the focus of this paper, the first in a series on this subject. Formalizing the concept and computation for linkage analysis, Elston and Stewart [1971; Human Heredity 21:523-542] introduced a likelihood function to capture relevant genetic information and a recursive algorithm for computing the likelihood function. However, the computing burden is prohibitive in processing complex pedigrees. Since that fundamental development, improving the computational algorithm and extending the method has been a dynamic area of research. The primary objective of this communication is to introduce a semiparametric method for linkage analysis. It is a particularly suitable approach with desirable properties for mapping complex traits that may be binary, continuous, and partially observed (i.e., censored). It incorporates candidate genes, environmental factors, and their interactions with the putative gene and is expected to be robust and efficient in comparison with likelihood-based methods. The properties of the estimates have been studied in finite samples with a limited simulation study. This method is illustrated with an application to family data contributed to the Breast Cancer Consortium.

Algorithms↗
PubMed1998

Endoscopic sinus surgery with magnetic resonance imaging guidance: initial patient experience.

We report the first endoscopic surgeries performed with patients under general anesthesia using intraoperative guidance with MRI. The procedures were experimental and intended to test (1) the unusual working environment of a unique new "open-configuration" MRI unit for head and neck surgery, and (2) real-time image guidance. Twelve patients underwent endoscopic sinus surgery while under general anesthesia in a new open MRI unit that provides the surgeon with access to the patient while imaging is performed. Eleven patients had chronic sinusitis (eight of them had bilateral disease), and one had a right nasoethmoid and antral tumor. All 12 surgeries were performed without complications. Both the endoscopic view and the MRI scans were available at the surgical field. The image plane was surgeon controlled, and the MRI updated images in as little as 14 seconds. MRI provided adequate visualization of both the disease and the related anatomy and allowed the surgeon to navigate during the procedure. The intraoperative data reflect the tissue changes during surgery and provide optimum feedback for surgical guidance. Although the operating environment poses some limitations, it has become apparent that intraoperative MRI has a role in the treatment of head and neck disorders and warrants further study.

Adult↗