Genetic mapping of a 17q chromosomal region linked to obesity phenotypes in the IRAS family study.

OBJECTIVE: Obesity is widely accepted to be influenced by both environmental and genetic factors. Several recent studies have used the positional cloning approach in an attempt to discover genes contributing to obesity. In the IRAS Family Study a genomewide scan was performed on 1425 individuals of Hispanic descent (90 extended pedigree families) to identify regions of the genome linked to obesity phenotypes. METHODS: Nonparametric QTL linkage analysis was performed using a variance components approach. The genome scan was performed in two phases: an initial genome scan in 45 families and a replication scan in 45 families. Fine mapping and candidate gene analyses were also performed. General estimating equations (GEE1) and quantitative pedigree disequilibrium tests (QPDT) were used for association analysis of single SNP and haplotype data. RESULTS: Evidence for linkage to obesity traits was observed in each scan on the long arm of chromosome 17. When data from both scans was combined, a region on chromosome 17q was identified with evidence of linkage to visceral adipose tissue (VAT; LOD 3.11), waist circumference (WAIST) (LOD 2.5) and body mass index (BMI) (LOD 2.81). Nine additional microsatellite markers were identified and genotyped on all Hispanic individuals, with a mean marker density of approximately 1 marker/3 cM. Evidence of linkage remained significant with LOD 3.05 for VAT, LOD 2.44 for BMI and LOD 1.92 for WAIST. Fine mapping analyses suggest the possibility of two different obesity loci. In addition, the LOD - 1 interval of the major VAT peak decreased from 83-108 to 95-111 cM. Three positional candidate genes under the peak: somatostatin receptor 2 (SSTR2), galanin receptor 2 (GALR2), and growth hormone bound protein receptor 2 (GRB2) were chosen for detailed evaluation. Multiple polymorphisms within each candidate were genotyped and tested for association with the obesity phenotypes. Little evidence of association was detected between polymorphisms and obesity traits. CONCLUSION: In conclusion, replication of linkage and fine mapping suggest that a region on chromosome 17q contains a gene (or genes) that contributes to the genetic etiology of obesity with the strongest evidence for linkage to VAT. Candidate genes in the region do not appear to account for the evidence of linkage. Additional studies are necessary to identify the obesity-related polymorphisms.

Quantitative trait loci for abdominal fat and BMI in Hispanic-Americans and African-Americans: the IRAS Family study.

OBJECTIVE: To conduct linkage analysis for body mass index (BMI, kg/m2), waist-to-hip ratio (WHR), visceral adipose tissue mass (VAT, cm2) and subcutaneous adipose tissue mass (SAT, cm2) using a whole genome scan. DESIGN: Cross-sectional family study. STUDY SUBJECTS: African-American families from Los Angeles (AA, n=21 extended pedigrees) and Hispanic-American families (HA) from San Antonio, TX (HA-SA, n=33 extended pedigrees) and San Luis Valley, CO (HA-SLV, n=12 extended pedigrees), totaling 1049 individuals in the Insulin Resistance and Atherosclerosis (IRAS) Family Study. MEASUREMENTS: VAT and SAT were measured using a computed tomography scan obtained at the fourth and fifth lumbar vertebrae. All phenotypes were adjusted for age, gender, and study center. VAT, SAT, and WHR were analyzed both unadjusted and adjusted for BMI. RESULTS: Significant linkage to BMI was found at D3S2387 (LOD=3.67) in African-Americans, and at D17S1290 in Hispanic-Americans (LOD=2.76). BMI-adjusted WHR was linked to 12q13-21 (D12S297 (LOD=2.67) and D12S1052 (LOD=2.60)) in Hispanic-Americans. The peak LOD score for BMI-adjusted VAT was found at D11S2006 (2.36) in Hispanic families from San Antonio. BMI-adjusted SAT was linked to D5S820 in Hispanic families (LOD=2.64). Evidence supporting linkage of WHR at D11S2006, VAT at D17S1290, and SAT at D1S1609, D3S2387, and D6S1056 was dependent on BMI, such that the LOD scores became nonsignificant after adjustment of these phenotypes for BMI. CONCLUSIONS: Our findings both replicate previous linkage regions and suggest novel regions in the genome that may harbor quantitative trait locis contributing to variation in measures of adiposity.

Fat distribution and metabolic changes are strongly correlated and energy expenditure is increased in the HIV lipodystrophy syndrome.

OBJECTIVE: To examine the relationships between protease inhibitor (PI) therapy, body fat distribution and metabolic disturbances in the HIV lipodystrophy syndrome. DESIGN: Cross-sectional study. SETTING: HIV primary care practices. PATIENTS: PI-treated patients with lipodystrophy (n= 14) and PI-treated (n= 13) and PI-naive (n= 5) patients without lipodystrophy. MAIN OUTCOME MEASURES: Body composition was assessed by physical examination, dual-energy X-ray absorptiometry and computed tomography. Insulin sensitivity (SI) was measured using the insulin-modified frequently sampled intravenous glucose tolerance test. Lipid profiles, other metabolic parameters, duration of HIV infection, CD4 lymphocyte counts, HIV-1 RNA load and resting energy expenditure (REE) were also assessed. RESULTS: PI-treated patients with lipodystrophy were significantly less insulin sensitive than PI-treated patients and PI-naive patients without any changes in fat distribution (SI(22) x 10(-4) (min(-1)/microU/ml) versus 3.2 x 10(-4) and 4.6 x 10(-4) (min(-1)/microU/ml), respectively; P < 0.001). Visceral adipose tissue area and other measures of central adiposity correlated strongly with metabolic disturbances as did the percent of total body fat present in the extremities; visceral adipose tissue was an independent predictor of insulin sensitivity and high density lipoprotein cholesterol levels. REE per kg lean body mass was significantly higher in the group with lipodystrophy compared to the groups without lipodystrophy (36.9 versus 31.5 and 29.4 kcal/kg lean body mass; P < 0.001), and SI was strongly correlated with and was an independent predictor of REE in this population. CONCLUSIONS: Body fat distribution and metabolic disturbances are strongly correlated in the HIV lipodystrophy syndrome and REE is increased.

Racial differences in amounts of visceral adipose tissue in young adults: the CARDIA (Coronary Artery Risk Development in Young Adults) study.

BACKGROUND: In several white populations, visceral adipose tissue (VAT) is a risk factor for development of type 2 diabetes and dyslipidemia. VAT can be accurately assessed by computed topography or magnetic resonance imaging, but is also estimated from anthropometric variables, such as waist-to-hip ratio, waist circumference, or sagittal diameter. To date, anthropometric variables have been used largely in whites and inadequate data are available to evaluate the validity of these variables in other groups. OBJECTIVES: The objectives of this study were to 1) determine whether amount of VAT in relation to total body fatness differs in different race and sex groups and 2) determine which anthropometric variables predict amount of VAT in different race and sex groups. DESIGN: We determined the amount and location of body fat, including assessment of VAT by computed tomography, in young adult white and black men and women participating in the 10-y follow-up of the CARDIA (Coronary Artery Risk Development in Young Adults) Study. RESULTS: Black men had less visceral fat (73.1+/-35.9 cm2) than white men (99.3+/-40 cm2), even when VAT was corrected for total body fatness. Black women were more obese than white women and thus had more visceral fat (75.1+/-37.5 compared with 58.6+/-35.9 cm2, respectively). This difference disappeared when corrected for total body fatness. CONCLUSIONS: Both waist circumference and sagittal diameter were good predictors of VAT in all groups. However, the nature of this relation differed such that race- and sex-specific equations will likely be required to estimate VAT from waist circumference or sagittal diameter.

Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group.

The Multiple Sclerosis Collaborative Research Group trial was a double-blind, randomized, multicenter, phase III, placebo-controlled study of interferon beta-1a (IFNbeta-1a; AVONEX) in relapsing forms of multiple sclerosis. Initial magnetic resonance imaging results have been published; this report provides additional results. Treatment with IFNbeta-1a, 30 microg once weekly by intramuscular injection, resulted in a significant decrease in the number of new, enlarging, and new plus enlarging T2 lesions over 2 years. The median increase in T2 lesion volume in placebo and IFNbeta-1a patients was 455 and 152 mm3, respectively, at 1 year and 1,410 and 628 mm3 at 2 years, although the treatment group differences did not reach statistical significance. For active patients, defined as those with gadolinium enhancement at baseline, the median change in T2 lesion volume in placebo and IFNbeta-1a patients was 1,578 and -12 mm3 and 2,980 and 1,285 mm3 at 1 and 2 years, respectively. Except for a minimal correlation of 0.30 between relapse rate and the number of gadolinium-enhanced lesions, correlations between MR and clinical measures at baseline and throughout the study were in general poor. Once weekly intramuscular IFNbeta-1a appears to impede the development of multiple sclerosis lesions at an early stage and has a favorable impact on the long-term sequelae of these inflammatory events as indicated by the slowed accumulation of T2 lesions.

Quantitation of T2 lesion load in multiple sclerosis with magnetic resonance imaging: a pilot study of a probabilistic neural network approach.

RATIONALE AND OBJECTIVES: To quantitate multiple sclerosis (MS) lesions in the brain by using computerized techniques. METHODS: MS lesions from five patients were quantitated with magnetic resonance (MR) imaging by using three approaches: a probabilistic neural network (PNN) approach, a semiautomated method that uses a bifeature space approach with operator intervention at each section, and the "gold standard" of manual outlining of lesions. Each patient underwent two MR studies in 1 day. RESULTS: The PNN approach allows reasonable quantitation of large data sets with minimal operator input. The mean intraobserver error for the PNN approach was competitive with the more time-consuming bifeature space approach (5.2% vs 4.4%, respectively). On average, both computer assisted methods performed better than the manual method (mean intraobserver error, 10.1%). CONCLUSION: The agreement between the two computerized quantitation approaches was good. The number of interactive steps was substantially reduced with the PNN technique, leading to minimal operator intervention time.

The visible human male: a technical report.

The National Library of Medicine's Visible Human Male data set consists of digital magnetic resonance (MR), computed tomography (CT), and anatomic images derived from a single male cadaver. The data set is 15 gigabytes in size and is available from the National Library of Medicine under a no-cost license agreement. The history of the Visible Human Male cadaver and the methods and technology to produce the data set are described.

Computation of left ventricular volume curves from gated blood pool studies without explicit use of edge detection algorithms: concise communication.

A new technique has been developed to compute left ventricular (LV) time activity curves from gated blood pool (GBP) studies without the use of manual, semiautomated or fully automated edge detection algorithms. The method utilizes the correlation of entropy calculated from the counts of a fixed region of interest covering the left ventricle during a cardiac cycle to compute the LV volume curve for a new patient. The new LV volume curve is obtained through interpolation of those volume curves of a data base which are associated with the closest variations in normalized entropy to the new one. The computed LV time activity curves agree with those obtained from manual or fully automated outlines of the left ventricle within 9 percent for the selected set of 67 patients demonstrating the potential of the method. The accuracy of calculated LV volume curves can be improved theoretically to any degree by increasing the number of cases in the data base of known statistical feature vectors associated with the LV images and LV volume curves. The new method for computation of LV curves is very efficient and robust when compared to traditional techniques.

The Visible Human data set: an image resource for anatomical visualization.

The National Library of Medicine (NLM) has long been a world leader in the archiving and distribution of the print-based images of biology and medicine. NLM has also been a pioneer in the use of computer systems to encode and distribute textual knowledge of the life sciences. NLM's Long Range Planning effort of 1985-86 foresaw a coming era where NLM's bibliographic and factual database services would be complemented by libraries of digital images, distributed over high speed computer networks and by high capacity physical media. The NLM Planning Panel on Electronic Imaging recommended that NLM should undertake the building of a digital image library consisting of computer-assisted tomography (CAT), magnetic resonance interferometry (MRI), and cryosection images of a representative, carefully selected and prepared male and female cadaver--the "Visible Human Project." The male Visible Human data set is now being made available through a license agreement with the NLM. A wide range of educational, diagnostic, treatment planning, and commercial uses is predicted. The Visible Human data set and its associated identification maps will serve as a "Boston Teapot" for medical imaging, a common public domain data set against which all medical imaging algorithms can be tested, and a cornerstone for future sets of related image libraries.

Quantitation of grey matter, white matter, and cerebrospinal fluid from spin-echo magnetic resonance images using an artificial neural network technique.

An operator independent technique has been developed to quantitate the volume of white matter (WM), grey matter (GM), and cerebrospinal fluid (CSF) using spin-echo magnetic resonance images. Using skull stripped spin-echo images, CSF was removed using an automated thresholding technique. The bimodal histogram of the remaining images was used to train a perceptron and a single hidden layer neural network to output the percentage of GM and WM in the image. The output values were compared with those of a semiautomated technique employing a least square fitting technique [graduated nonconvexity algorithm (GNC)] applied to the bimodal histogram. This semiautomated technique allowed for intervention by the radiologist. Fourteen normal volunteers with eight contiguous slices each were analyzed. The individual percentages of WM, GM, and CSF of 40 slices from five subjects not used in the training set as well as the total percentages of GM, WM, and CSF in each individual were predicted using the two artificial network architectures. GM, WM, and CSF percentages were predicted within 7% for individual slices while total percentages of WM, GM, and CSF were computed accurately with an absolute error of less than 5% when compared to the semiautomated technique involving a trained neuroradiologist.

Assessment of ultrasonic computed tomography in symptomatic breast patients by discriminant analysis.

From 95 subjects imaged with both speed of sound and attenuation ultrasonic computed tomography (UCT), quantitative analyses are presented on 40 cases where unequivocal correlating clinical diagnoses are available. Using four attenuation and speed of sound parameters from different regions of interest in the breast, a linear discriminator detects cancer with approximately 90% sensitivity and specificity. Increased confidence in the predictive power of this small study is given by a modern test of predictive power (jackknifing) and by the fact that diagnostic discrimination remains as high as 85% when only two parameters are employed--attenuation and speed of sound in the lesion minus those values in the remaining central mammary tissues. Speed of sound images appear particularly useful in older, fatty breasts where pulse echo ultrasound is particularly lacking. While UCT in the form studied here is not likely to receive wide clinical acceptance in the near future, a combined UCT/pulse echo system might find wide clinical utility if it can be sufficiently convenient and inexpensive.

Lesion detectability in ultrasonic computed tomography of symptomatic breast patients.

From 95 subjects imaged with both speed of sound and attenuation ultrasonic computed tomography (UCT), analyses were performed on 40 cases for which unequivocal clinical diagnoses were available for correlation. This paper describes the UCT image characteristics and addresses the hypothesis that carcinomas and other lesions can be detected and localized by means of simple visual criteria or lesion characteristics that are quantitative relative to those of other breast tissues in the same patient. The most useful within-patient criterion was selection of the solid mass with the highest speed of sound in either breast (12 of 12 carcinomas). Architectural asymmetry between breasts in the three types of images was a significant contributing factor in visual image interpretation in seven of the eight cancer patients in whom there were comparable images of both breasts. Solid masses were discriminated by attenuation coefficient and pulse echo criteria. Our results did not substantiate the hypothesis that the average speed of sound throughout the cancer containing breast would be higher than in the contralateral breast. These results are better than might be expected from pulse echo imaging alone on this population. However, clinical implementation probably should be deferred until the technique is made more convenient and less expensive, or more accurate with a greater promise for diagnosis of minimal cancers.

Basic principles of magnetic resonance imaging--an update.

Magnetic resonance (MR) imaging technology has undergone many technologic advances over the past few years. Many of these advances were stimulated by the wealth of information emerging from nuclear magnetic resonance research in the areas of new and optimal scanning methods and radio-frequency coil design. Other changes arose from the desire to improve image quality, ease siting restrictions and generally facilitate the clinical use of MR equipment. Many questions, however, remain unanswered. Perhaps the most controversial technologic question involves the optimal field strength required for imaging or spectroscopic applications or both. Other issues include safety and clinical efficacy. Technologic issues affect all aspects of MR use including the choice of equipment, examination procedure and image interpretation. Thus, an understanding of recent changes and their theoretic basis is necessary.

A tissue-equivalent upper abdominal phantom.

The first prototypes of an abdominal phantom have been constructed. The phantom is intended for eventual use in training diagnostic ultrasound personnel and in demonstrating commercial equipment. It is constructed from plastics believed to be stable and approximately tissue-equivalent at room temperature. Abdominal structures are formed from a dispersion of a polystyrene butadiene plastic in mineral oil. Polyvinyl chloride particles are incorporated to provide the desired attenuation coefficients and scattering levels. B-scans of the phantom produced realistic images, although problems associated with scanning technique and somewhat high phantom attenuation were noted. Very useful phantoms should result from relatively simple improvements in construction techniques.

Breast imaging in coronal planes with simultaneous pulse echo and transmission ultrasound.

Clear delineation of breast architecture was achieved with compound pulse echo ultrasound imaging in which the images were acquired in the coronal planes used for quantitative transmission ultrasonic computed tomography. Since most connective tissue planes in the breast radiate toward the nipple, compound scans from the sides of the breast record normal interfaces more consistently and reveal greater symmetries in normal portions of relatively full breasts than do conventional scans in sagittal or transverse planes. Simultaneous acquisition of the pulse echo images and images representing the local ultrasound attenuation coefficient and speed of ultrasound suggested complementary role for reflection and through-transmission images in breast cancer detection. The high quality of pulse echo images in coronal planes provides the potential for more complete pulse echo diagnosis and the basis for spatial correlation of lesions viewed in pulse echo and ultrasonic computed tomograms. These observations may permit routine ultrasonic computed tomography of the breast in the clinical setting.