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Author Summary Individuals with thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune thyroid diseases (AITD), which are common in the general population and associated with increased cardiovascular, metabolic and psychiatric morbidity and mortality. As the causative genes of TPOAbs and AITD remain largely unknown, we performed a genome-wide scan for TPOAbs in 18,297 individuals, with replication in 8,990 individuals. Significant associations were detected with variants at TPO, ATXN2, BACH2, MAGI3, and KALRN. Individuals carrying multiple risk variants also had a higher risk of increased thyroid-stimulating hormone levels (including subclinical and overt hypothyroidism), and a decreased risk of goiter. The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, and the MAGI3 variant was also associated with an increased risk of hypothyroidism. This first genome-wide scan for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. These results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which individuals are particularly at risk of developing clinical thyroid dysfunction. Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,9

Background Automated systems for the quantitative analysis of three-dimensional (3D) sets of intravascular ultrasound (IVUS) images have been developed to reduce the time required to perform volumetric analyses; however, 3D image reconstruction by these nongated systems is frequently hampered by cyclic artifacts. Methods and Results We used an ECG-gated 3D IVUS image acquisition workstation and a dedicated pullback device in atherosclerotic coronary segments of 30 patients to evaluate (1) the feasibility of this approach of image acquisition, (2) the reproducibility of an automated contour detection algorithm in measuring lumen, external elastic membrane, and plaque+media cross-sectional areas (CSAs) and volumes and the cross-sectional and volumetric plaque+media burden, and (3) the agreement between the automated area measurements and the results of manual tracing. The gated image acquisition took 3.9±1.5 minutes. The length of the segments analyzed was 9.6 to 40.0 mm, with 2.3±1.5 side branches per segment. The minimum lumen CSA measured 6.4±1.7 mm2, and the maximum and average CSA plaque+media burden measured 60.5±10.2% and 46.5±9.9%, respectively. The automated contour-detection required 34.3±7.3 minutes per segment. The differences between these measurements and manual tracing did not exceed 1.6% (SD<6.8%). Intraobserver and interobserver differences in area measurements (n=3421; r=.97 to.99) were <1.6% (SD<7.2%); intraobserver and interobserver differences in volumetric measurements (n=30; r=.99) were <0.4% (SD<3.2%). Conclusions ECG-gated acquisition of 3D IVUS image sets is feasible and permits the application of automated contour detection to provide reproducible measurements of the lumen and atherosclerotic plaque CSA and volume in a relatively short analysis time.

Intravascular ultrasound (rvUS) is a new imaging mOdality providing real-time, crosssectional, high-resolution images of the arterial lumen and vessel wall. In contrast to conventional x-ray angiography that only displays silhouette views of the vessel lumen, IVUS imaging permits visualization of lesion morphology and accurate measurements of arterial cross-sectional dimensions in patients. These unique capabilities have led to many important clinical applications including quantitative assessment of the severity, restenosis, progression of atherosclerosis, selection and guidance of catheterbased therapeutic procedures and short- and long-term evaluation of the outcome of an intravascular intervention. Like the progress of other medial imaging modalities, the advent of IVUS techniques has brought in new challenges in the field of signal and image processing. Quantitative analysis of IVUS images requires the identification of arterial structures such as the lumen and plaque within an image. Manual contour tracing is well known to be time consuming and subjective. Development of an automated contour detection method may improve the reproducibility of quantitative IVUS and avoid a tedious manual procedure. Computerized three-dimensional (3D) reconstruction of an IVUS image series may extend the tomographic data to a more powerful volumetric assessment of the vessel segment. Obviously, this could not be achieved without the advance of 3D image processing techniques. Furthermore, it is demonstrated that processing of the original radio frequency (RF) echo signals provides an efficient means to improve the IVUS image quality as well as a new approach to extract volumetric flow information. The goals of the studies reported in this thesis are therefore directed toward development of video image and RF signal processing techniques for image enhancement, automated contour detection, 3D reconstruction and flow imaging. In this chapter several IVUS scanning mechanisms and some

BACKGROUND: Volumetric intravascular ultrasound (IVUS) assessment provides complementary information on atherosclerotic plaques. The volumes can be calculated by applying Simpson's rule to cross-sectional area data of multiple IVUS images, acquired with a fixed sample spacing, which is the distance (along the vessel's axis) between two images. OBJECTIVE: To evaluate the effect of different sample spacings on the results of volumetric IVUS measurements. METHODS: A stepwise electrocardiographically gated IVUS image-acquisition and automated three-dimensional analysis approach was applied to 26 patients. Twenty-eight coronary segments with mild-to-moderate coronary atherosclerosis were examined. Volumetric measurements of five images per mm (i.e. sample spacing 0.2 mm), representing a complete scanning of the coronary segment, were considered the optimal standard, against which volumetric measurements of three, one, and one-half images per mm (i.e. larger sample spacings) were compared. RESULTS: The lumen, total vessel, and

Quantitative analysis of arterial dimensions from high frequency intravascular ultrasound images (30 MHz) may be hampered by strong blood scattering. Replacement of blood by saline is one method to provide a clear view of the arterial lumen; another method is that of temporal averaging of successive ultrasound images. The accuracy of this latter method was tested by comparing the lumen area measurements on the temporal-averaged image, with the data of the same cross-section obtained from the single-frame and saline-filled images. The mean lumen area measured on the temporal-averaged images was similar to that measured on the single-frame images (mean difference: −0.02 ± 1.16 mm2; p = ns). The mean lumen ar