bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Magnetic Resonance Imaging of Activation in Subcortical Auditory Pathway
Authors: Yetkin F. Zerrin , Roland Peter S. , Mendelsohn Dianne B. , Purdy Phillip D.
Published: December 2003

Objectives Functional magnetic resonance imaging (fMRI) has been used to investigate activation of the auditory cortex; however, assessment of activation in the subcortical auditory pathway has been challenging. The aim of this study was to examine neural correlates of cortical and subcortical auditory activation evoked by pure‐tone stimulus using silent fMRI.

Study Design Prospective analysis

Methods Seventeen normal‐hearing volunteers (7 male, 10 female; age range, 14–37 yrs) underwent silent fMRI. An audiometer was used to deliver pure tones of 1000 Hz to the left ear. Pure tones were presented at hearing thresholds determined in the scanner. Brain regions showing increased activation during pure‐tone stimulus presentation were mapped and auditory activations exceeding P < .001 were included in the analysis.

Results Pure‐tone stimuli evoked bilateral activation in cortical regions of the transverse and superior temporal gyri and the planum temporale. Activation in subcortical structures included the medial geniculate body, inferior colliculus, lateral lemniscus, superior olivary complex, and cochlear nucleus.

Conclusions Silent functional magnetic resonance imaging findings documented the feasibility of detecting activation elicited by pure tone along the cortical and subcortical auditory pathway. The use of this technique in the assessment of disorders with auditory dysfunction merits further investigation.
Epidermal Growth Factor Receptor in Undifferentiated Carcinoma of the Nasopharynx
Authors: Leong Jern‐Lin , Loh Kwok Seng , Putti Thomas Choudhary , Goh Boon Cher , Tan Luke Kim Siang
Published: December 2003

Objectives To determine the expression levels of epidermal growth factor receptor (EGFR) and its prognostic value in undifferentiated carcinoma (UC) of the nasopharynx.

Study Design A prospective study of 75 patients diagnosed with UC over a 4‐year period in a tertiary care hospital.

Materials and Methods Postnasal space biopsies were obtained and processed, and immunohistochemical staining was performed. The over‐expression of EGFR was measured, and the expression levels were statistically analyzed with the clinical and pathologic variables. Disease‐free and overall survival analyses were performed.

Results There were 62 (82.7%) specimens that showed over‐expression of EGFR levels. Over‐expression of EGFR correlated significantly only with primary tumor size (P = .007). Age, sex, positive smoking and family history, presence of nodal metastasis, distant metastasis, and Epstein‐Barr virus serology titers were not significantly correlated with over‐expression of EGFR. Both 54‐month disease‐free and 56‐month overall survivals were not associated with EGFR over‐expression.

Conclusion The frequency of over‐expression of EGFR in UC is similar to other squamous cell carcinoma (SCC) of the head and neck region. Only primary tumor size is independently correlated with over‐expression of EGFR. EGFR over‐expression does not affect disease‐free and overall survival.
The Impact of Severe Acute Respiratory Syndrome on Otorhinolaryngological Services at The Prince of Wales Hospital in Hong Kong
Authors: Vlantis Alexander C. , Tsang Raymond K. Y. , Wong Duncan K. K. , Woo John K. S. , van Hasselt C. Andrew
Published: December 2003

Objectives/Hypothesis The objective was to describe the impact of severe acute respiratory syndrome (SARS) on the services of the division of otorhinolaryngology—head and neck surgery at an academic tertiary referral hospital in Hong Kong.

Study Design Descriptive.

Methods Records of general and subspecialty outpatient attendance, ward admissions, ward bed occupancy, and elective and emergency surgery were obtained for the period since the SARS outbreak and for an equivalent period before the outbreak. The changes in these parameters were determined against the background of new SARS cases.

Results Since the outbreak of SARS in March 2003, the weekly outpatient clinic attendance has declined by 59%, the number of operations performed by 79%, the average ward bed occupancy rate by 79% and the daily admission rate by 84%. A dramatic increase of 300% in the number of patients defaulting on their outpatient appointments was recorded.

Conclusion The substantial decrease in otorhinolaryngological services at an academic tertiary referral hospital in Hong Kong has been multifaceted. The decrease in attendance at the outpatient clinics reflects the increased number of patients defaulting on their appointments. Nonessential elective surgery was suspended soon after the outbreak, accounting for the decrease in the number of surgical procedures performed and partially for the decrease in ward bed occupancy and ward admissions. The temporary closure of the accident and emergency department contributed to the decrease in ward admissions and emergency surgical procedures. The reduced service offered by the hospital is having an impact on the quality of care available to patients with non–life‐threatening otorhinolaryngological conditions.
Pharyngeal Entry through the Vallecula
Authors: Wei William I. , Ho W.K. , Ng Raymond W.M.
Published: December 2003

The authors describe a technique of entry into the vallecula with the guide of a small Deaver retractor inserted transorally, beyond the tongue base, into the vallecula. The tip of the Deaver directs the surgeon to the pharyngotomy site and allows pharyngeal entry and access without damaging structures in the region. This technique is particularly useful in total laryngectomy with or without pharyngectomy and is applicable whenever entry to the pharynx through the vallecula is indicated.
The
trp
RNA-Binding Attenuation Protein of
Bacillus subtilis
Regulates Translation of the Tryptophan Transport Gene
trpP
(
yhaG
) by Blocking Ribosome Binding
Authors: Yakhnin Helen , Zhang Hong , Yakhnin Alexander V. , Babitzke Paul
Published: December 2003

Expression of the
Bacillus subtilis
tryptophan biosynthetic genes (
trpEDCFBA
and
pabA
[
trpG
]) is regulated in response to tryptophan by TRAP, the
trp
RNA-binding attenuation protein. TRAP-mediated regulation of the tryptophan biosynthetic genes includes a transcription attenuation and two distinct translation control mechanisms. TRAP also regulates translation of
trpP
(
yhaG
), a single-gene operon that encodes a putative tryptophan transporter. Its translation initiation region contains triplet repeats typical of TRAP-regulated mRNAs. We found that regulation of
trpP
and
pabA
is unaltered in a
rho
mutant strain. Results from filter binding and gel mobility shift assays demonstrated that TRAP binds specifically to a segment of the
trpP
transcript that includes the untranslated leader and translation initiation region. While the affinities of TRAP for the
trpP
and
pabA
transcripts are similar, TRAP-mediated translation control of
trpP
is much more extensive than for
pabA
. RNA footprinting revealed that the
trpP
TRAP binding site consists of nine triplet repeats (five GAG, three UAG, and one AAG) that surround and overlap the
trpP
Shine-Dalgarno (S-D) sequence and translation start codon. Results from toeprint and RNA-directed cell-free translation experiments indicated that tryptophan-activated TRAP inhibits TrpP synthesis by preventing binding of a 30S ribosomal subunit. Taken together, our results establish that TRAP regulates translation of
trpP
by blocking ribosome binding. Thus, TRAP coordinately regulates tryptophan synthesis and transport by three distinct mechanisms: attenuation transcription of the
trpEDCFBA
operon, promoting formation of the
trpE
S-D blocking hairpin, and blocking ribosome binding to the
pabA
and
trpP
transcripts.
Molecular and Functional Characterization of a Unique Sucrose Hydrolase from
Xanthomonas axonopodis
pv. glycines
Authors: Kim Hong-Suk , Park Hyoung-Joon , Heu Sunggi , Jung Jin
Published: December 2003

A novel sucrose hydrolase (SUH) from
Xanthomonas axonopodis
pv. glycines, a causative agent of bacterial pustule disease on soybeans, was studied at the functional and molecular levels. SUH was shown to act rather specifically on sucrose (

K
m

= 2.5 mM) but not on sucrose-6-phosphate. Protein analysis of purified SUH revealed that, in this monomeric enzyme with an estimated molecular mass of 70,223 ± 12 Da, amino acid sequences determined for several segments have corresponding nucleotide sequences in
XAC3490
, a protein-coding gene found in the genome of
X. axonopodis
pv. citri. Based on this information, the SUH gene, consisting of an open reading frame of 1,935 bp, was cloned by screening a genomic library of
X. axonopodis
pv. glycines 8ra. Database searches and sequence comparison revealed that SUH has significant homology to some family 13 enzymes, with all of the crucial invariant residues involved in the catalytic mechanism conserved, but it shows no similarity to known invertases belonging to family 32.
suh
expression in
X. axonopodis
pv. glycines requires sucrose induction, and insertional mutagenesis resulted in an absence of sucrose-inducible sucrose hydrolase activity in crude protein extracts and a sucrose-negative phenotype. Recombinant SUH, overproduced in
Escherichia coli
and purified, was shown to have the same enzymatic characteristics in terms of kinetic parameters.
Comparative Genomics of
Rickettsia prowazekii
Madrid E and Breinl Strains
Authors: Ge Hong , Chuang Yao-Yu Eric , Zhao Shuping , Tong Min , Tsai Mong-Hsun , Temenak Joseph J. , Richards Allen L. , Ching Wei-Mei
Published: December 2003

Rickettsia prowazekii
, the causative agent of epidemic typhus, has been responsible for millions of human deaths. Madrid E is an attenuated strain of
R. prowazekii
, while Breinl is a virulent strain. The genomic DNA sequence of Madrid E has recently been published. To study the genomic variations between Madrid E (reference) and Breinl (test) DNAs, cohybridization experiments were performed on a DNA microarray containing all 834 protein-coding genes of Madrid E. Of the 834 genes assessed, 24 genes showed 1.5- to 2.0-fold increases in hybridization signals in Breinl DNA compared to Madrid E DNA, indicating the presence of genomic variations in ∼3% of the total genes. Eighteen of these 24 genes are predicted to be involved in different functions. Southern blot analysis of five genes,
virB4
,
ftsK
,
rfbE
,
lpxA
, and
rpoH
, suggested the presence of an additional paralog(s) in Breinl, which might be related to the observed increase in hybridization signals. Studies by real-time reverse transcription-PCR revealed an increase in expression of the above-mentioned five genes and five other genes. In addition to the elevated hybridization signals of 24 genes observed in the Breinl strain, one gene (
rp084
) showed only 1/10 the hybridization signal of Madrid E. Further analysis of this gene by PCR and sequencing revealed a large deletion flanking the whole
rp084
gene and part of the
rp083
gene in the virulent Breinl strain. The results of this first rickettsial DNA microarray may provide some important information for the elucidation of pathogenic mechanisms of
R. prowazekii
.
Cloning and Characterization of Acetohydroxyacid Synthase from
Bacillus stearothermophilus
Authors: Porat Iris , Vinogradov Michael , Vyazmensky Maria , Lu Chung-Dar , Chipman David M. , Abdelal Ahmed T. , Barak Ze'ev
Published: December 2003

Five genes from the
ilv-leu
operon from
Bacillus stearothermophilus
have been sequenced. Acetohydroxyacid synthase (AHAS) and its subunits were separately cloned, purified, and characterized. This thermophilic enzyme resembles AHAS III of
Escherichia coli
, and regulatory subunits of AHAS III complement the catalytic subunit of the AHAS of
B. stearothermophilus
, suggesting that AHAS III is functionally and evolutionally related to the single AHAS of gram-positive bacteria.
THE STABILIZING EFFECT OF POSTERIOR FIXATIONS IN A DESTABILIZED ATLANTOAXIAL COMPLEX MODEL IN CANINES
Authors: Chang Ching-Hong , Lee E-Jian , Chang Guan-Liang , Chang Jia-Hao , Hung Yu-Chang , Lee Ming-Yang
Published: December 2003

Purpose: This study was conducted to evaluate the kinematic responses and the restorative effectiveness of three posterior fixations in a canine atlantoaxial ( C1-2) complex model.

Methods: Nine canine ligamentous C1-2complexes were non-destructively tested in an intact condition, after ligamentous destabilization, and after bilateral stabilization with each of three posterior fixation methods: (1) Halifax inter-laminar clamps; (2) sub-laminar wiring; and (3) individual fixation of the C1lateral mass and the C2pedicle with screws and plates. Specimens were subjected to a relevantly applied loads through a loading frame rigidly attached to the C1. Two sets of three markers was separately attached to the mounting jigs of the C1and the C2to record the spatial locations after each loading step with a Vicron 370 system. The load-deformation data were analyzed.

Results: Under a realistic loading paradigm, destabilized canine C1-2complex had 3-dimensional motion ranges highly consistent with the corresponding values observed in destabilized cadaveric human C1-2complex following a non-destructive loading paradigm. All the three posterior fixations significantly restricted the motion range of axial rotation loads (P<0.05). However, fixation either with posterior inter-articular screws and plates or inter-laminar clamps also effectively restricted the motion ranges of flexion/extension and lateral bending loads, whereas posterior wiring did not.

Conclusion: We described a destabilized canine C1-2complex model. Under a realistic loading paradigm, the model had kinematic analogue of destabilized human C1-2complex. Our results indicated that posterior stabilization using inter-articular fixation techniques or inter-laminar clamps could effectively restrict hypermotility caused by C1-2ligamentous destabilization, and, therefore, appeared to be reliable fixation methods. In contrast, posterior wiring alone would preserve more residual motions, and, thus, might need other adjunctive fixations to offer an optimal condition for solid bony fusion.
Global Burden of Disease (GBD) for Hepatitis C
Authors:   The Global Burden of Hepatitis C Working Group
Published: December 2003

Hepatitis C virus (HCV) infection is now a global public health issue. However, the global burden of disease attributable to HCV infection is unknown. The objectives of this WHO informal consultation included the following: (1) defining a strategy to estimate the global burden of disease (GBD) associated with HCV infection in terms of morbidity and mortality, (2) describing the natural history of HCV infection in terms of morbidity and mortality, and (3) identifying areas for which more research is needed. The GBD project is an attempt to examine all causes of morbidity and mortality using an approach common to all conditions. The World Health Organization (WHO) already has estimated the burden of disease associated with hepatitis B virus (HBV) infection and is now about to conduct the same analysis for HCV infection. A review has been conducted to estimate the prevalence of HCV infection by age, gender, and region. These figures can be used to estimate incidence, although there are a number of areas of uncertainty. Combined with natural history parameters, incidence estimates could be used to estimate the future burden due to current infections. However, the present model is not validated and requires calibration before it can be used. A consensus was reached over the strategies to be used to (1) estimate the current burden due to past infections and (2) estimate the future burden due to current infections. Provisional expert consensus was reached over natural history parameters and cofactors that influence them. However, systematic literature reviews and meta‐analysis are preferable for obtaining estimates to be included in models. Areas deserving future research include (1) obtaining a better estimate of HCV infection prevalence by age groups, (2) characterizing the various morbidity states associated with HCV infection and their disability weights, (3) understanding the long‐term natural history of HCV infection beyond 20 years after infection, and (4) estimating the prevalence (and numbers of) of HCV infection among the drug‐using population worldwide. A working group was created to address unmet needs and to assist the WHO in estimating the GBD associated with HCV infection.
Pharmacokinetic and Pharmacodynamic Evaluation of a Novel Proton Pump Inhibitor, YH1885, in Healthy Volunteers
Authors: Yu Kyung‐Sang , Bae Kyun‐Seop , Shon Ji‐Hong , Cho Joo‐Youn , Yi So‐Young , Chung Jae‐Yong , Lim Hyeong‐Seok , Jang In‐Jin , Shin Sang‐Goo , Song Keun‐Seog , Moon Byoung‐Seok
Published: December 2003

To evaluate the pharmacokinetic and pharmacodynamic characteristics of YH1885, a novel proton pump inhibitor, a single‐blind, randomized, placebo‐controlled, dose‐rising, parallel‐group study was conducted in 46 healthy volunteers. The volunteers were randomly allocated to single dose groups of 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg (6 subjects per dose, including 2 placebos) or to multiple‐dose groups of 150 mg and 300 mg (once‐daily dosing for 7 days; 8 subjects per dose, including 2 placebos). The multiple‐dose study was conducted separately after the single‐dose study. YH1885 was administered orally after overnight fasting. Serial blood samples, urine samples, and pharmacodynamic measurements were taken. Drug concentrations in plasma and urine were determined by liquid chromatography/mass spectrometry (LC/MS). Pharmacodynamic changes were evaluated by ambulatory intragastric pH monitoring and by serial measurements of serum gastrin concentrations. Assessments of safety and tolerability also were made. Plasma concentrations of YH1885 reached peak levels 1.3 to 2.5 hours after single‐dose administration and then declined monoexponentially with a terminal half‐life (t1/2) of 2.2 to 2.4 hours in dosage groups up to 200 mg in the single‐dose study. YH1885 showed linear pharmacokinetic characteristics, and little accumulation occurred after multiple administrations. The parent drug was not detected in urine. Dose‐related pharmacological effects were obvious for dose groups of 150 mg and higher in the single‐dose study. The mean intragastric pH and the percentage of time at pH > 4 were significantly increased. The onset of drug effect was rapid, and maximal effects were observed on the first day of administration during multiple dosing. Serum gastrin levels also showed rapid increases during dosing but with a weak dose‐effect relationship. Neither serious nor dose‐limiting adverse effects were observed. YH1885 was found to be safe and well tolerated and effectively inhibited acid secretion with dose‐dependent increases in intragastric pH. The acid‐suppressing efficacy of YH1885 needs to be further evaluated in patients with gastric acid‐related diseases.
Absolute Bioavailability and Pharmacokinetics of Treprostinil Sodium Administered by Acute Subcutaneous Infusion
Authors: Wade Michael , Baker F. Jo , Roscigno Robert , DellaMaestra Wayne , Hunt Thomas L. , Lai Allen A.
Published: December 2003

The objective of this study was to evaluate the absolute bioavailability and acute pharmacokinetics of treprostinil sodium administered by continuous, short‐term subcutaneous infusion in normal subjects. Fifteen healthy volunteers received treprostinil via an intravenous infusion at 15 ng/kg/ min over 150 minutes, followed by a 5‐ to 7‐day washout and a subcutaneous infusion at the same rate administered over 150 minutes. Serial plasma samples were collected predosing, during dosing, and postdosing, and plasma treprostinil concentration levels were measured by a validated liquid chromatography atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) method with a lower limit of quantitation (LLOQ) of 25 pg/mL. Acute administration of treprostinil administered by subcutaneous infusion at a rate of 15 ng/kg/min for 150 minutes achieved a mean Cmax of 1.47 ng/mL. Mean AUC∞ values for intravenous and subcutaneous dosing were 3.52 and 3.97 ng•h/mL, respectively, resulting in a mean apparent absolute bioavailability of 113% for subcutaneous administration. It was possible that the area under of the curve for the intravenous administration was underestimated because most of the terminal elimination phase could not be documented due to the LLOQ of the assay. The mean apparent elimination half‐life of treprostinil following subcutaneous administration was 1.38 hours, compared to 0.87 hours following intravenous administration. It was concluded that treprostinil administered by subcutaneous administration is completely absorbed, with a slightly longer half‐life compared to intravenously administered treprostinil.
Genomic regions linked to alcohol consumption in the Framingham Heart Study
Authors: Bergen Andrew W , Yang Xiaohong Rose , Bai Yan , Beerman Michael B , Goldstein Alisa M , Goldin Lynn R
Published: December 2003

Background

Pedigree, demographic, square-root transformed maximum alcohol (SRMAXAPD) and maximum cigarette (MAXCPD) consumption, and genome-wide scan data from the Framingham Heart Study (FHS) were used to investigate genetic factors that may affect alcohol and cigarette consumption in this population-based sample.

Results

A significant sister:sister correlation greater than spouse correlation was observed for MAXCPD only. Single-point sib-pair regression analysis provided nominal evidence for linkage of loci to both SRMAXAPD and MAXCPD consumption traits, with more significant evidence of linkage to SRMAXAPD than to MAXCPD. One genomic region, chr9q21.11, exhibits significant multi-point sib-pair regression to SRMAXAPD.

Conclusion

SRMAXAPD exhibits greater evidence for genetic linkage than does MAXCPD in the FHS sample. Four regions of the genome exhibiting nominal evidence for linkage to SRMAXAPD in the FHS sample correspond to regions of the genome previously identified as linked to alcoholism or related traits in the family data set ascertained on individuals affected with alcohol dependence known as COGA.
Multiple genome-wide analyses of smoking behavior in the Framingham Heart Study
Authors: Goode Ellen L , Badzioch Michael D , Kim Helen , Gagnon France , Rozek Laura S , Edwards Karen L , Jarvik Gail P
Published: December 2003

Background

Cigarette smoking behavior may have a genetic basis. We assessed evidence for quantitative trait loci (QTLs) affecting the maximum number of cigarettes smoked per day, a trait meant to quantify this behavior, using data collected over 40 years as part of the Framingham Heart Study's original and offspring cohorts.

Results

Heritability was estimated to be approximately 21% using variance components (VC) methods (SOLAR), while oligogenic linkage and segregation analysis based on Bayesian Markov chain Monte Carlo (MCMC) methods (LOKI) estimated a mean of two large QTLs contributing approximately 28% and 20%, respectively, to the trait's variance. Genome-wide parametric (FASTLINK) and VC linkage analyses (SOLAR) revealed several LOD scores greater than 1.0, with peak LOD scores using both methods on chromosomes 2, 17, and 20; multi-point MCMC methods followed up on these chromosomes. The most robust linkage results were for a QTL between 65 and 84 cM on chromosome 20 with signals from multiple sex- and age-adjusted analyses including two-point LOD scores of 1.30 (parametric) and 1.07 (heritability = 0.17, VC) at 70.51 cM, a multi-point LOD score of 1.50 (heritability = 0.20, VC) at 84 cM, and an intensity ratio of 12.0 (MCMC) at 65 cM.

Conclusion

Familial aggregation of the maximum number of cigarettes smoked per day was consistent with a genetic component to this behavior, and oligogenic segregation analyses using MCMC suggested two important QTLs. Linkage signals on chromosome 20 between 65 and 84 cM were seen using multiple analytical methods. No linkage result, however, met genome-wide statistical significance criteria, and the true relationship between these regions and smoking behavior remains unclear.
Mapping susceptibility loci for alcohol consumption using number of grams of alcohol consumed per day as a phenotype measure
Authors: Ma Jennie Z , Zhang Dong , Dupont Randolph T , Dockter Michael , Elston Robert C , Li Ming D
Published: December 2003

Background

There is substantial evidence for a significant genetic component to the risk for alcoholism. However, susceptibility loci or genes for alcohol dependence remain largely unknown. To identify susceptibility loci for alcohol dependence, we selected 329 extended families from the Framingham Heart Study population in which at least one family member reported alcohol consumption during the interview in 1970–1971, and performed genome-wide linkage analyses using various analytical methods.

Results

Multi-point sib-pair regression analysis using the SIBPAL program of S.A.G.E. provided strong evidence for linkage of alcohol dependence to chromosomes 9 (p-value < 0.0001) and weak evidence to chromosomes 15 and 16 (p-value < 0.005). To confirm these findings, we re-analyzed the same data set by various methods implemented in GENEHUNTER and found that only one region was significant with a LOD score > 2.0 by the variance-component method. This region is located on chromosome 9 between markers GATA21F05 and GATA81C04.

Conclusion

Analyses of the Framingham Heart Study population provided evidence of genetic susceptibility loci for alcohol dependence on chromosomes 9, 15, and 16. The genomic region identified on chromosome 9 was particularly interesting because the region has also been previously reported to be linked to alcohol dependence in the American Indian population by another group.
Are there mappable genes for family resemblance for the magnitude of intra-individual variation in systolic blood pressure?
Authors: Lin Jennifer , Hinrichs Anthony , Suarez Brian K
Published: December 2003

Background

The genetic regulation of variation in intra-individual fluctuations in systolic blood pressure over time is poorly understood. Analysis of the magnitude of the average fluctuation of a person's systolic blood pressure around his or her age-adjusted trend line, however, shows moderate, albeit significant, family resemblance in Cohort 1 of the Framingham Heart Study. To determine whether genomic regions affecting this phenotype could be identified, we pursued a "model-free" multipoint quantitative linkage analysis.

Results

Two different linkage methods revealed multiple nominally significant signals, two to four of which are "replicated" in Cohort 2. When both cohorts are assembled into extended pedigrees, three linkage signals remain nominally significant by one or both methods.

Conclusion

Any or all of the genomic regions in the vicinity of D5S1456, D11S2359, and D20S470 may contain elements that regulate systolic blood pressure homeostasis.
The genetics of cross-sectional and longitudinal body mass index
Authors: Strug Lisa , Sun Lei , Corey Mary
Published: December 2003

There has been a lack of consistency in detecting chromosomal loci that are linked to obesity-related traits. This may be due, in part, to the phenotype definition. Many studies use a one-time, single measurement as a phenotype while one's weight often fluctuates considerably throughout adulthood. Longitudinal data from the Framingham Heart Study were used to derive alternative phenotypes that may lead to more consistent findings. Body mass index (BMI), a measurement for obesity, is known to increase with age and then plateau or decline slightly; the decline phase may represent a threshold or survivor effect. We propose to use the weight gain phase of BMI to derive phenotypes useful for linkage analysis of obesity. Two phenotypes considered in the present study are the average of and the slope of the BMI measurements in the gain phase (gain mean and gain slope). For comparison, we also considered the average of all BMI measurements available (overall mean). Linkage analysis using the gain mean phenotype exhibited two markers with LOD scores greater than 3, with the largest score of 3.52 on chromosome 4 at ATA2A03. In contrast, no LOD scores greater than 3 were observed when overall mean was used. The gain slope produced weak evidence for linkage on chromosome 4 with a multipoint LOD score of 1.77 at GATA8A05. Our analysis shows how omitting the decline phase of BMI in the definition of obesity phenotypes can result in evidence for linkage which might have been otherwise overlooked.
Empirically derived phenotypic subgroups – qualitative and quantitative trait analyses
Authors: Wilcox Marsha A , Wyszynski Diego F , Panhuysen Carolien I , Ma Qianli , Yip Agustin , Farrell John , Farrer Lindsay A
Published: December 2003

Background

The Framingham Heart Study has contributed a great deal to advances in medicine. Most of the phenotypes investigated have been univariate traits (quantitative or qualitative). The aims of this study are to derive multivariate traits by identifying homogeneous groups of people and assigning both qualitative and quantitative trait scores; to assess the heritability of the derived traits; and to conduct both qualitative and quantitative linkage analysis on one of the heritable traits.

Methods

Multiple correspondence analysis, a nonparametric analogue of principal components analysis, was used for data reduction. Two-stage clustering, using both k-means and agglomerative hierarchical clustering, was used to cluster individuals based upon axes (factor) scores obtained from the data reduction. Probability of cluster membership was calculated using binary logistic regression. Heritability was calculated using SOLAR, which was also used for the quantitative trait analysis. GENEHUNTER-PLUS was used for the qualitative trait analysis.

Results

We found four phenotypically distinct groups. Membership in the smallest group was heritable (38%, p < 1 × 10-6) and had characteristics consistent with atherogenic dyslipidemia. We found both qualitative and quantitative LOD scores above 3 on chromosomes 11 and 14 (11q13, 14q23, 14q31). There were two Kong & Cox LOD scores above 1.0 on chromosome 6 (6p21) and chromosome 11 (11q23).

Conclusion

This approach may be useful for the identification of genetic heterogeneity in complex phenotypes by clarifying the phenotype definition prior to linkage analysis. Some of our findings are in regions linked to elements of atherogenic dyslipidemia and related diagnoses, some may be novel, or may be false positives.
Power of maximum HLOD tests to detect linkage to obesity genes
Authors: Yoo Yun Joo , Huo Yanling , Ning Yuming , Gordon Derek , Finch Stephen , Mendell Nancy R
Published: December 2003

Background

We investigate the power of heterogeneity LOD test to detect linkage when a trait is determined by several major genes using Genetic Analysis Workshop 13 simulated data. We consider three traits, two of which are disease-causing traits: 1) the rate of change in body mass index (BMI); and 2) the maximum BMI; and 3) the disease itself (hypertension). Of interest is the power of "HLOD2", the maximum heterogeneity LOD obtained upon maximizing over the two genetic models.

Results

Using a trait phenotype Obesity Slope, we observe that the power to detect the two markers closest to the two genes (S1, S2) at the 0.05 level using HLOD2 is 13% and 10%. The power of HLOD2 for Max BMI phenotype is 12% and 9%. The corresponding values for the Hypertension phenotype are 8% and 6%.

Conclusion

The power to detect linkage to the slope genes is quite low. But the power using disease-related traits as a phenotype is greater than the power using the disease (hypertension) phenotype.
Comparison of longitudinal variance components and regression-based approaches for linkage detection on chromosome 17 for systolic blood pressure
Authors: Andrade Mariza de , Olswold Curtis
Published: December 2003

We compare two methods to detect genetic linkage by using serial observations of systolic blood pressure in pedigree data from the Framingham Heart Study focusing on chromosome 17. The first method is a variance components (VC) approach that incorporates longitudinal pedigree data, and the second method is a regression-based approach that summarizes all longitudinal measures in one single measure. No evidence of linkage was found either using the VC longitudinal approach or the regression-based approach, except when all time points were used from Cohorts 1 and 2 and only subjects aged 25 and 75 years were included.
Multilevel modeling for the analysis of longitudinal blood pressure data in the Framingham Heart Study pedigrees
Authors: Briollais Laurent , Tzontcheva Anjela , Bull Shelley
Published: December 2003

Background

The data arising from a longitudinal familial study have a complex correlation structure that cannot be modeled using classical methods for the analysis of familial data at a single time point.

Methods

To fit the longitudinal systolic blood pressure (SBP) pedigree data arising from the Framingham Heart Study, we proposed to use multilevel modeling. That approach was used to distinguish multiple levels of information with individual repeated measurements (Level 1) being made within individuals (Level 2), and individuals clustered within pedigrees (Level 3). Residuals from the subject-specific and pedigree-specific regression models were summed both for the mean SBP and slope of SBP change over time, in order to define two new outcomes that were then used in a genome-wide linkage analysis.

Results

Evidence for linkage for the two outcomes (mean SBP and slope) was found in several chromosomal regions with a maximum LOD score of 3.6 on chromosome 8 and 3.5 on chromosome 17 for the mean SBP, and 2.5 on chromosome 1 for SBP slope. However, the linkage on chromosome 8 was only detected when the sample was restricted to subjects between age 25 and 75 and with at least four exams (Cohort 1) or 3 exams (Cohort 2).

Discussion

Multilevel modeling is a powerful approach to detect genes involved in complex traits when longitudinal data are available. It allows for complex hierarchical data structure to be taken into account and therefore, a better partitioning of random within-individual variation from other sources of variability (genetic or nongenetic).
Comparison of the linkage results of two phenotypic constructs from longitudinal data in the Framingham Heart Study: analyses on data measured at three time points and on the average of three measurements
Authors: Cheng Rong , Park Naeun , Hodge Susan E , Juo Suh-Hang Hank
Published: December 2003

Background

Family studies are often conducted in a cross-sectional manner without long-term follow-up data. The relative contribution of a gene to a specific trait could change over the lifetime. The Framingham Heart Study offers a unique opportunity to investigate potential gene × time interaction. We performed linkage analysis on the body mass index (BMI) measured in 1970, 1978, and 1986 for this project.

Results

We analyzed the data in two different ways: three genome-wide linkage analyses on each exam, and one genome-wide linkage analysis on the mean of the three measurements. Variance-component linkage analyses were performed by the SOLAR program. Genome-wide scans show consistent evidence of linkage of quantitative trait loci (QTLs) on chromosomes 3, 6, 9, and 16 in three measurements with a maximum multipoint LOD score > 2.2. However, only chromosome 9 has a LOD score = 2.14 when the mean values were analyzed. More interestingly, we found potential gene × environment interactions: increasing LOD scores with age on chromosomes 3, 9, and 16 and decreasing LOD scores on chromosome 6 in the three exams.

Conclusion

The results indicate two points: 1) it is possible that a gene (or genes) influencing BMI is (are) up- or down-regulated as people aged due to aging process or changes in lifestyle, environments, or genetic epistasis; 2) using mean values from longitudinal data may reduce the power to detect linkage and may have no power to detect gene × time, and/or gene × gene interactions.
Segregation and linkage analysis for longitudinal measurements of a quantitative trait
Authors: Gee Conway , Morrison John L , Thomas Duncan C , Gauderman W James
Published: December 2003

We present a method for using slopes and intercepts from a linear regression of a quantitative trait as outcomes in segregation and linkage analyses. We apply the method to the analysis of longitudinal systolic blood pressure (SBP) data from the Framingham Heart Study. A first-stage linear model was fit to each subject's SBP measurements to estimate both their slope over time and an intercept, the latter scaled to represent the mean SBP at the average observed age (53.7 years). The subject-specific intercepts and slopes were then analyzed using segregation and linkage analysis. We describe a method for using the standard errors of the first-stage intercepts and slopes as weights in the genetic analyses. For the intercepts, we found significant evidence of a Mendelian gene in segregation analysis and suggestive linkage results (with LOD scores ≥ 1.5) for specific markers on chromosomes 1, 3, 5, 9, 10, and 17. For the slopes, however, the data did not support a Mendelian model, and thus no formal linkage analyses were conducted.
Linkage analysis of longitudinal data
Authors: Suh Young Ju , Park Taesung , Cheong Soo Yeon
Published: December 2003

Background

We propose a statistical model for linkage analysis of the longitudinal data. The proposed model is a mixed model based on the new Haseman and Elston model and allows several random effects. Specifically, the proposed model includes a random effect for correlation among sib pairs having one sibling in common, and one for the correlation among siblings from the same parents.

Results

The proposed model was applied to the analysis of the Genetic Analysis Workshop 13 simulated data set for a quantitative trait of the systolic blood pressure. A simple independence model and two kinds of random effects models yielded good power for detecting linkage for these data sets, while the random effects models performed slightly better than the independence model. Both random effects models showed similar performance.

Conclusions

The proposed models seem not only quite useful in detecting linkage with the longitudinal data for the trait but also quite flexible. They can handle a wide class of correlation structures. Models with a more general class of covariance structure are desirable.
Genetic Analysis Workshop 13: Simulated longitudinal data on families for a system of oligogenic traits
Authors: Daw E Warwick , Morrison John , Zhou Xiaojun , Thomas Duncan C
Published: December 2003

The Genetic Analysis Workshop 13 simulated data aimed to mimic the major features of the real Framingham Heart Study data that formed Problem 1, but under a known inheritance model and with 100 replicates, so as to allow evaluation of the statistical properties of various methods. The pedigrees used were the 330 real pedigree structures (comprising 4692 individuals) with some minor changes to protect confidentiality. Fifty trait genes and 399 microsatellite markers were simulated by gene dropping on 22 autosomal chromosomes. Assuming random ascertainment of families, a system of eight longitudinal quantitative traits (designed to be similar to those in the real data) was generated with a wide range of heritabilities, including some pleiotropic and interactive effects. Genes could affect either the baseline level or the rate of change of the phenotype. Hypertension diagnosis and treatment were simulated with treatment availability, compliance, and efficacy depending on calendar year. Nongenetic traits of smoking and alcohol were generated as covariates for other traits. Death was simulated as a hazard rate depending upon age, sex, smoking, cholesterol, and systolic blood pressure.

After the complete data were simulated, missing data indicators were generated based on logistic models fitted to the real data, involving the subject's history of previous missing values, together with that of their spouses, parents, siblings, and offspring, as well as marital status, only-child indicators, current value at certain simulated traits, and the data collection pattern on the cohort into which each subject was ascertained.
Age-Stratified QTL Genome Scan Analyses for Anthropometric Measures
Authors: Beck Stephanie R , Brown W Mark , Williams Adrienne H , Pierce June , Rich Stephen S , Langefeld Carl D
Published: December 2003

With the availability of longitudinal data, age-specific (stratified) or age-adjusted genetic analyses have the potential to localize different putative trait influencing loci. If age does not influence the locus-specific penetrance function within the range examined, age-stratified analyses will tend to yield comparable results for an individual trait. However, age-stratified results should vary across age strata when the locus-specific penetrance function is age dependent. In this paper, age-stratified and age-adjusted quantitative trait loci (QTL) linkage analyses were contrasted for height, weight, body mass index (BMI), and systolic blood pressure on a subset of the Framingham Heart Study. The strata comprised individuals with data present in each of three age groups: 31–49, 50–60, 61–79. Genome-wide QTL analyses were performed using SOLAR. Over all ages, a linkage signal for height was detected on chromosome 14q11.2 near marker GATA74E02A (LOD for ages 31–49 = 2.38, LOD for ages 50–60 = 1.84, LOD for ages 61–79 = 2.45). Evidence of linkage to BMI in the 31–49 age group was found on chromosome 3q22 (GATA3C02, LOD = 2.89, p = 0.0003) at the same location as the signal for weight (LOD = 3.10, p = 0.0002). Linkage was also supported on chromosome 1p22.1 for BMI (LOD = 2.21, p = 0.0014) and weight (LOD = 2.47, p = 0.0007) in the 31–49 age group. Our age-stratified results suggest that QTL that are expressed over long periods of time and affecting multiple, correlated traits may be identified using genome scan and variance-component methodology to help detect early and/or late gene expression.
Comparison of year-of-exam- and age-matched estimates of heritability in the Framingham Heart Study data
Authors: Mathias Rasika A , Roy-Gagnon Marie-Hélène , Justice Cristina M , Papanicolaou George J , Fan Yu Ti , Pugh Elizabeth W , Wilson Alexander F
Published: December 2003

Several different approaches can be used to examine generational and temporal trends in family studies. The measurement of offspring and parents can be made over a short period of time with parents and offspring having quite different ages, or measurements can be made at the same ages but with decades between parent and offspring measures. A third approach, used in the Framingham Heart Study, has repeated examinations across a broad range of age and time, and provides a unique opportunity to compare these approaches. Parents and offspring were matched both on (year of exam) and on age. Heritability estimates for systolic blood pressure, body mass index, height, weight, cholesterol, and glucose were obtained by regressing offspring on midparent values with and without adjustment for age. Higher estimates of heritability were obtained for age-matched than for year-of-exam-matched data for all traits considered. For most traits, estimates of the heritability of the change over time (slope) of the trait were near zero. These results suggest that the optimal design to identify genetic effects in traits with large age-related effects may be to measure parents and offspring at similar ages and not to rely on age-adjustment or longitudinal measures to account for these temporal effects.
Stability of exploratory multivariate data modeling in longitudinal data
Authors: Sengul Haydar , Barmada M Michael
Published: December 2003

Exploratory data-driven multivariate analysis provides a means of investigating underlying structure in complex data. To explore the stability of multivariate data modeling, we have applied a common method of multivariate modeling (factor analysis) to the Genetic Analysis Workshop 13 (GAW13) Framingham Heart Study data. Given the longitudinal nature of the data, multivariate models were generated independently for a number of different time points (corresponding to cross-sectional clinic visits for the two cohorts), and compared. In addition, each multivariate model was used to generate factor scores, which were then used as a quantitative trait in variance component-based linkage analysis to investigate the stability of linkage signals over time. We found surprisingly good correlation between factor models (i.e., predicted factor structures), maximum LOD scores, and locations of maximum LOD scores (0.81< ρ <0.94 for factor scores; ρ >0.99 for peak locations; and 0.67< ρ <0.93 for peak LOD scores). Furthermore, the regions implicated by linkage analysis with these factor scores have also been observed in other studies, further validating our exploratory modeling.
Variance components linkage analysis for adjusted systolic blood pressure in the Framingham Heart Study
Authors: Byng Martyn C , Fisher Sheila A , Lewis Cathryn M , Whittaker John C
Published: December 2003

We performed variance components linkage analysis in nuclear families from the Framingham Heart Study on nine phenotypes derived from systolic blood pressure (SBP). The phenotypes were the maximum and mean SBP, and SBP at age 40, each analyzed either uncorrected, or corrected using two subsets of epidemiological/clinical factors. Evidence for linkage to chromosome 8p was detected with all phenotypes except the uncorrected maximum SBP, suggesting this region harbors a gene contributing to variation in SBP.
An examination of the genotyping error detection function of SIMWALK2
Authors: Badzioch Michael D , DeFrance Hawkins B , Jarvik Gail P
Published: December 2003

This investigation was undertaken to assess the sensitivity and specificity of the genotyping error detection function of the computer program SIMWALK2. We chose to examine chromosome 22, which had 7 microsatellite markers, from a single simulated replicate (330 pedigrees with a pattern of missing genotype data similar to the Framingham families). We created genotype errors at five overall frequencies (0.0, 0.025, 0.050, 0.075, and 0.100) and applied SIMWALK2 to each of these five data sets, respectively assuming that the total error rate (specified in the program), was at each of these same five levels. In this data set, up to an assumed error rate of 10%, only 50% of the Mendelian-consistent mistypings were found under any level of true errors. And since as many as 70% of the errors detected were false-positives, blanking suspect genotypes (at any error probability) will result in a reduction of statistical power due to the concomitant blanking of correctly typed alleles. This work supports the conclusion that allowing for genotyping errors within likelihood calculations during statistical analysis may be preferable to choosing an arbitrary cut-off.
Pedigree and genotype errors in the Framingham Heart Study
Authors: Brush Gerry , Almasy Laura
Published: December 2003

The pedigree and genotype data from the Framingham Heart Study were examined for errors. Errors in 21 of 329 pedigrees were detected with the program PREST, and of these the errors in 16 pedigrees were resolved. Genotyping errors were then detected with SIMWALK2. Five Mendelian errors were found following the pedigree corrections. Double-recombinant errors were more common, with 142 being detected at mistyping probabilities of 0.25 or greater.