Genetic analysis of Tourette syndrome suggesting major gene effect.

Data on Gilles de la Tourette syndrome are analyzed by multiple threshold models in inheritance that incorporate sex effect. The polygenic-multifactorial model is rejected. Single major locus inheritance can account for the data, although many of the occurrences of Tourette are due to nongenetic phenocopies. In both models, males and females share a common genetic environmental liability, but the less prevalent sex, that is, females, has a higher genetic loading for the disorder. The predicted population prevalences in the single major locus model are 2.3% for males and 0.8% for females. The implications for genetic and biological research in Tourette syndrome are discussed.     

Schizophrenia: the testing of genetic models by pedigree analysis.

Simulated pedigrees of schizophrenia generally show a clear peak in their likelihood surface corresponding to analysis by the genetic models, which served as the basis for the simulation. The likelihood surface obtained with real data permits determination of the allelic frequency and the selection of an optimal one-locus, two-locus, and four-locus model. These three models have certain features in common, notably, a relatively high frequency of the allele predisposing to schizophrenia (about 20%) and a relatively low index of genetic determination (23%--34%). However, direct likelihood comparisons do not permit distinctions between the one-locus, two-locus, and four-locus models. The most likely interpretation of this finding is that the etiology of schizophrenia is heterogeneous or even nongenetic. However, a simple model with a single completely recessive locus and incomplete penetrance in the homozygote also produces a flat likelihood surface closely resembling that obtained with the real data. With reservation, this single-locus model may be put forward as a potentially useful working hypothesis.     

An evaluation of three statistics of structured exploratory data analysis

The power of structured exploratory data analysis (SEDA) to discriminate among major genic, polygenic, and nongenetic determination of phenotypes was investigated using computer simulation. Three classes of SEDA indices (the major gene index, the offspring between parents function, and the midparent-child correlation coefficient) were evaluated. These three statistics, in combination, were reasonably sensitive in detecting the presence of a major locus and in discriminating between phenotypes with genetic effects and those with no genetic component. However, they were unable to discriminate between major genic and polygenically determined phenotypic models.     

Improving the Efficiency of Abdominal Aortic Aneurysm Wall Stress Computations

An abdominal aortic aneurysm is a pathological dilation of the abdominal aorta, which carries a high mortality rate if ruptured. The most commonly used surrogate marker of rupture risk is the maximal transverse diameter of the aneurysm. More recent studies suggest that wall stress from models of patient-specific aneurysm geometries extracted, for instance, from computed tomography images may be a more accurate predictor of rupture risk and an important factor in AAA size progression. However, quantification of wall stress is typically computationally intensive and time-consuming, mainly due to the nonlinear mechanical behavior of the abdominal aortic aneurysm walls. These difficulties have limited the potential of computational models in clinical practice. To facilitate computation of wall stresses, we propose to use a linear approach that ensures equilibrium of wall stresses in the aneurysms. This proposed linear model approach is easy to implement and eliminates the burden of nonlinear computations. To assess the accuracy of our proposed approach to compute wall stresses, results from idealized and patient-specific model simulations were compared to those obtained using conventional approaches and to those of a hypothetical, reference abdominal aortic aneurysm model. For the reference model, wall mechanical properties and the initial unloaded and unstressed configuration were assumed to be known, and the resulting wall stresses were used as reference for comparison. Our proposed linear approach accurately approximates wall stresses for varying model geometries and wall material properties. Our findings suggest that the proposed linear approach could be used as an effective, efficient, easy-to-use clinical tool to estimate patient-specific wall stresses.     

Investigation of material modeling in fluid–structure interaction analysis of an idealized three-layered abdominal aorta: aneurysm initiation and fully developed aneurysms

Different material models for an idealized three-layered abdominal aorta are compared using computational techniques to study aneurysm initiation and fully developed aneurysms. The computational model includes fluid–structure interaction (FSI) between the blood vessel and the blood. In order to model aneurysm initiation, the medial region was degenerated to mimic the medial loss occurring in the inception of an aneurysm. Various cases are considered in order to understand their effects on the initiation of an abdominal aortic aneurysm. The layers of the blood vessel were modeled using either linear elastic materials or Mooney–Rivlin (otherwise known as hyperelastic) type materials. The degenerated medial region was also modeled in either linear elastic or hyperelastic-type materials and assumed to be in the shape of an arc with a thin width or a circular ring with different widths. The blood viscosity effect was also considered in the initiation mechanism. In addition, dynamic analysis of the blood vessel was performed without interaction with the blood flow by applying time-dependent pressure inside the lumen in a three-layered abdominal aorta. The stresses, strains, and displacements were compared for a healthy aorta, an initiated aneurysm and a fully developed aneurysm. The study shows that the material modeling of the vessel has a sizable effect on aneurysm initiation and fully developed aneurysms. Different material modeling of degeneration regions also affects the stress–strain response of aneurysm initiation. Additionally, the structural analysis without considering FSI (called noFSI) overestimates the peak von Mises stress by 52% at the interfaces of the layers.     

The Helsinki Rat Microsurgical Sidewall Aneurysm Model

Experimental saccular aneurysm models are necessary for testing novel surgical and endovascular treatment options and devices before they are introduced into clinical practice. Furthermore, experimental models are needed to elucidate the complex aneurysm biology leading to rupture of saccular aneurysms.Several different kinds of experimental models for saccular aneurysms have been established in different species. Many of them, however, require special skills, expensive equipment, or special environments, which limits their widespread use. A simple, robust, and inexpensive experimental model is needed as a standardized tool that can be used in a standardized manner in various institutions.The microsurgical rat abdominal aortic sidewall aneurysm model combines the possibility to study both novel endovascular treatment strategies and the molecular basis of aneurysm biology in a standardized and inexpensive manner. Standardized grafts by means of shape, size, and geometry are harvested from a donor rat''s descending thoracic aorta and then transplanted to a syngenic recipient rat. The aneurysms are sutured end-to-side with continuous or interrupted 9-0 nylon sutures to the infrarenal abdominal aorta.We present step-by-step procedural instructions, information on necessary equipment, and discuss important anatomical and surgical details for successful microsurgical creation of an abdominal aortic sidewall aneurysm in the rat.     

Abdominal Aortic Aneurysms

Aneurysms are common in our increasingly elderly population, and are a major threat to life and limb. Until the advent of vascular reconstructive techniques, aneurysm patients were subject to an overwhelming risk of death from exsanguination. The first successful repair of an abdominal aortic aneurysm using an interposed arterial homograft was reported by Dubost in 1952. A milestone in the evolution of vascular surgery, this event and subsequent diagnostic, operative and prosthetic graft refinements have permitted patients with an unruptured abdominal aortic aneurysm to enjoy a better prognosis than patients with almost any other form of major systemic illness.     

Robust variance-components approach for assessing genetic linkage in pedigrees.

To assess evidence for genetic linkage from pedigrees, I developed a limited variance-components approach. In this method, variability among trait observations from individuals within pedigrees is expressed in terms of fixed effects from covariates and effects due to an unobservable trait-affecting major locus, random polygenic effects, and residual nongenetic variance. The effect attributable to a locus linked to a marker is a function of the additive and dominance components of variance of the locus, the recombination fraction, and the proportion of genes identical by descent at the marker locus for each pair of sibs. For unlinked loci, the polygenic variance component depends only on the relationship between the relative pair. Parameters can be estimated by either maximum-likelihood methods or quasi-likelihood methods. The forms of quasi-likelihood estimators are provided. Hypothesis tests derived from the maximum-likelihood approach are constructed by appeal to asymptotic theory. A simulation study showed that the size of likelihood-ratio tests was appropriate but that the monogenic component of variance was generally underestimated by the likelihood approach.     

Segregation analysis of continuous phenotypes by using higher sample moments.

The present article discusses the use of computational methods based on generalized estimating equations (GEE), as a potential alternative to full maximum-likelihood methods, for performing segregation analysis of continuous phenotypes by using randomly selected family data. The method that we propose can estimate effect and degree of dominance of a major gene in the presence of additional nongenetic or polygenetic familial associations, by relating sample moments to their expectations calculated under the genetic model. It is known that all parameters in basic major-gene models cannot be identified, for estimation purposes, solely in terms of the first two sample moments of data from randomly selected families. Thus, we propose the use of higher (third order) sample moments to resolve this identifiability problem, in a pseudo-profile likelihood estimation scheme. In principle, our methods may be applied to fitting genetic models by using complex pedigrees and for estimation in the presence of missing phenotype data for family members. In order to assess its statistical efficiency we compare several variants of the method with each other and with maximum-likelihood estimates provided by the SAGE computer package in a simulation study.     

Long term relative survival after surgery for abdominal aortic aneurysm in Western Australia: population based study

Objective: To determine the long term relative survival of all patients who had surgery for abdominal aortic aneurysm in Western Australia during 1985-94. Design: Population based study. Setting: Western Australia. Subjects: All patients who had had surgery for abdominal aortic aneurysm in Western Australia during 1985-94. Main outcome measures: Morbidity and mortality data of patients admitted and surgically treated for abdominal aortic aneurysm in Western Australia during 1985-94. Elective, ruptured, and acute non-ruptured cases were analysed separately. Independent analyses for sex and patients aged 80 years or more were also undertaken. Postoperative (>30 days) relative survival was assessed against age and sex matched controls. Results: Overall, 1475 (1257 men, 218 women) cases were identified. The crude five year survival after elective surgery, including deaths within 30 days of surgery, was 79% for both men and women. When compared with a matched population the five year relative survival after elective surgery was 94.9% (95% confidence interval 89.9% to 99.9%) for men but only 88.0% (76.3% to 99.7%) for women. The five year relative survival of those aged 80 years and over was good: 116.6% (89.1% to 144.0%) compared with 92.4% (87.7% to 97.0%) for those under 80 years of age (men and women combined). Cardiovascular disease caused 57.8% of the 341 deaths after 30 days. Conclusion: In a condition such as abdominal aortic aneurysm, which occurs in elderly patients, relative survival is more clinically meaningful than crude survival. The five year relative survival in cases of elective and ruptured abdominal aortic aneurysm was better in men than in women. This is probably because of greater comorbidity in women with abdominal aortic aneurysm and this deserves more attention in the future. The long term survival outcome in octogenarians supports surgery in selected cases.

Key messages

• Background mortality for conditions such as abdominal aortic aneurysm in elderly patients needs to be taken into account when assessing long term survival after surgery
• Relative survival methodology can correct for background mortality
• The five year relative survival for patients surviving beyond 30 days of elective surgery for abdominal aortic aneurysm was 95% for men and 88% for women
• For octogenarians, five year survival after elective surgery was greater than that expected of an age matched population
• Age over 80 years should not preclude consideration for elective surgery for abdominal aortic aneurysm

     

A New Murine Model of Endovascular Aortic Aneurysm Repair

Endovascular aneurysm exclusion is a validated technique to prevent aneurysm rupture. Long-term results highlight technique limitations and new aspects of Abdominal aortic aneurysm (AAA) pathophysiology. There is no abdominal aortic aneurysm endograft exclusion model cheap and reproducible, which would allow deep investigations of AAA before and after treatment. We hereby describe how to induce, and then to exclude with a covered coronary stentgraft an abdominal aortic aneurysm in a rat. The well known elastase induced AAA model was first reported in 1990¹ in a rat, then described in mice². Elastin degradation leads to dilation of the aorta with inflammatory infiltration of the abdominal wall and intra luminal thrombus, matching with human AAA. Endovascular exclusion with small covered stentgraft is then performed, excluding any interactions between circulating blood and the aneurysm thrombus. Appropriate exclusion and stentgraft patency is confirmed before euthanasia by an angiography thought the left carotid artery. Partial control of elastase diffusion makes aneurysm shape different for each animal. It is difficult to create an aneurysm, which will allow an appropriate length of aorta below the aneurysm for an easy stentgraft introduction, and with adequate proximal and distal neck to prevent endoleaks. Lots of failure can result to stentgraft introduction which sometimes lead to aorta tear with pain and troubles to stitch it, and endothelial damage with post op aorta thrombosis. Giving aspirin to rats before stentgraft implantation decreases failure rate without major hemorrhage. Clamping time activates neutrophils, endothelium and platelets, and may interfere with biological analysis.     

Segregation analysis reveals evidence of a major gene for Alzheimer disease.

In an attempt to resolve the relative influences of major genes, multifactorial heritability, and cohort effects on the susceptibility to Alzheimer disease (AD), complex segregation analysis was performed on 232 nuclear families. All families were consecutively ascertained through a single proband who was referred for diagnostic evaluation of a memory disorder. The results suggest that susceptibility to AD is determined, in part, by a major autosomal dominant allele with an additional multifactorial component. Single-locus, polygenic, sporadic, and no-transmission models, as well as recessive inheritance of the major effect, were significantly rejected. Excess transmission from the heterozygote was marginally significant and probably reflects the presence of phenocopies or perhaps the existence of two or more major loci for AD. The frequency of the AD susceptibility allele was estimated to be .038, but the major locus accounts for only 24% of the transmission variance, indicating a substantial role for other genetic and nongenetic mechanisms in the causation of AD.     

Stereoscopically observed deformations of a compliant abdominal aortic aneurysm model

A new experimental setup has been implemented to precisely measure the deformations of an entire model abdominal aortic aneurysm (AAA). This setup addresses a gap between the computational and experimental models of AAA that have aimed at improving the limited understanding of aneurysm development and rupture. The experimental validation of the deformations from computational approaches has been limited by a lack of consideration of the large and varied deformations that AAAs undergo in response to physiologic flow and pressure. To address the issue of experimentally validating these calculated deformations, a stereoscopic imaging system utilizing two cameras was constructed to measure model aneurysm displacement in response to pressurization. The three model shapes, consisting of a healthy aorta, an AAA with bifurcation, and an AAA without bifurcation, were also evaluated with computational solid mechanical modeling using finite elements to assess the impact of differences between material properties and for comparison against the experimental inflations. The device demonstrated adequate accuracy (surface points were located to within 0.07?mm) for capturing local variation while allowing the full length of the aneurysm sac to be observed at once. The experimental model AAA demonstrated realistic aneurysm behavior by having cyclic strains consistent with reported clinical observations between pressures 80 and 120?mm Hg. These strains are 1-2%, and the local spatial variations in experimental strain were less than predicted by the computational models. The three different models demonstrated that the asymmetric bifurcation creates displacement differences but not cyclic strain differences within the aneurysm sac. The technique and device captured regional variations of strain that are unobservable with diameter measures alone. It also allowed the calculation of local strain and removed rigid body motion effects on the strain calculation. The results of the computations show that an asymmetric aortic bifurcation created displacement differences but not cyclic strain differences within the aneurysm sac.     

A maximum likelihood-based method for mining major genes affecting a quantitative character

In this article, we present a maximum likelihood-based analytical approach for detecting a major gene of large effect on a quantitative trait in a progeny population derived from a mating design. Our analysis is based on a mixed genetic model specifying both major gene and background polygenic inheritance. The likelihood of the data is formulated by combining the information about population behaviors of the major gene during hybridization and its phenotypic distribution densities. The EM algorithm is implemented to obtain maximum likelihood estimates for population and quantitative genetic parameters of the major locus. This approach is applied to detect an overdominant gene governing stem volume growth in a factorial mating design of aspen trees. It is suggested that further molecular genetic research toward mapping single genes affecting aspen growth and production based on the same experimental data has a high probability of success.     

An indication of major genes affecting hip and elbow dysplasia in four Finnish dog populations

The aim of the study was to assess the possible existence of major genes influencing hip and elbow dysplasia in four dog populations. A Bayesian segregation analysis was performed separately on each population. In total, 34 140 dogs were included in the data set. Data were analysed with both a polygenic and a mixed inheritance model. Polygenic models included fixed and random environmental effects and additive genetic effects. To apply mixed inheritance models, the effect of a major gene was added to the polygenic models. The major gene was modelled as an autosomal biallelic locus with Mendelian transmission probabilities. Gibbs sampling and a Monte Carlo Markov Chain algorithm were used. The goodness-of-fit of the different models were compared using the residual sum-of-squares. The existence of a major gene was considered likely for hip dysplasia in all the breeds and for elbow dysplasia in one breed. Several procedures were followed to exclude the possible false detection of major genes based on non-normality of data: permuted datasets were analysed, data-transformations were applied, and residuals were judged for normality. Allelic effects at the major gene locus showed nearly to complete dominance, with a recessive, unfavourable allele in both traits. Relatively high estimates of the frequencies of unfavourable alleles in each breed suggest that considerable genetic progress would be possible by selection against major genes. However, the major genes that are possibly affecting hip and elbow dysplasia in these populations will require further study.     

Flow behaviour in an asymmetric compliant experimental model for abdominal aortic aneurysm

An experimental study was carried out on asymmetrical abdominal aortic aneurysm (AAA) to analyse the physiological flows involved. Velocity measurements were performed using particle image velocimetry. Resting and exercise flow rates were investigated in models with rigid and compliant walls to assess the parameters affecting the flow behaviour. The secondary flow patterns, and especially the evolution of the vortices within the AAA, were found to be highly dependent on both the flow waveforms and the wall behaviour. Vortices impacts on the distal walls of the AAA occur in the compliant model and can increase the local pressure on the AAA walls and thus increase the wall stresses; AAA wall stresses are one of the most important factors contributing to ruptured aneurysm.     

Long Telomeres in Blood Leukocytes Are Associated with a High Risk of Ascending Aortic Aneurysm

Ascending aortic aneurysm is a connective tissue disorder. Even though multiple novel gene mutations have been identified, risk profiling and diagnosis before rupture still represent a challenge. There are studies demonstrating shorter telomere lengths in the blood leukocytes of abdominal aortic aneurysm patients. The aim of this study was to measure whether relative telomere lengths are changed in the blood leukocytes of ascending aortic aneurysm patients. We also studied the expression of telomerase in aortic tissue samples of ascending aortic aneurysms. Relative lengths of leukocyte telomeres were determined from blood samples of patients with ascending aortic aneurysms and compared with healthy controls. Telomerase expression, both at the level of mRNA and protein, was quantified from the aortic tissue samples. Mean relative telomere length was significantly longer in ascending aortic aneurysm blood samples compared with controls (T/S ratio 0.87 vs. 0.61, p<0.001). Expressions of telomerase mRNA and protein were elevated in the aortic aneurysm samples (p<0.05 and p<0.01). Our study reveals a significant difference in the mean length of blood leukocyte telomeres in ascending aortic aneurysm and controls. Furthermore, expression of telomerase, the main compensating factor for telomere loss, is elevated at both the mRNA and protein level in the samples of aneurysmal aorta. Further studies will be needed to confirm if this change in telomere length can serve as a tool for assessing the risk of ascending aortic aneurysm.     

Identification of in vivo material and geometric parameters of a human aorta: toward patient-specific modeling of abdominal aortic aneurysm

Recent advances in computational modeling of vascular adaptations and the need for their extension to patient-specific modeling have introduced new challenges to the path toward abdominal aortic aneurysm modeling. First, the fundamental assumption in adaptation models, namely the existence of vascular homeostasis in normal vessels, is not easy to implement in a vessel model built from medical images. Second, subjecting the vessel wall model to the normal pressure often makes the configuration deviate from the original geometry obtained from medical images. To address those technical challenges, in this work, we propose a two-step optimization approach; first, we estimate constitutive parameters of a healthy human aorta intrinsic to the material by using biaxial test data and a weighted nonlinear least-squares parameter estimation method; second, we estimate the distributions of wall thickness and anisotropy using a 2-D parameterization of the vessel wall surface and a global approximation scheme integrated within an optimization routine. A direct search method is implemented to solve the optimization problem. The numerical optimization method results in a considerable improvement in both satisfying homeostatic condition and minimizing the deviation of geometry from the original shape based on in vivo images. Finally, the utility of the proposed technique for patient-specific modeling is demonstrated in a simulation of an abdominal aortic aneurysm enlargement.     

Hemodynamics of the mouse abdominal aortic aneurysm

The abdominal aortic aneurysm (AAA) is a significant cause of death and disability in the Western world and is the subject of many clinical and pathological studies. One of the most commonly used surrogates of the human AAA is the angiotensin II (Ang II) induced model used in mice. Despite the widespread use of this model, there is a lack of knowledge concerning its hemodynamics; this study was motivated by the desire to understand the fluid dynamic environment of the mouse AAA. Numerical simulations were performed using three subject-specific mouse models in flow conditions typical of the mouse. The numerical results from one model showed a shed vortex that correlated with measurements observed in vivo by Doppler ultrasound. The other models had smaller aneurysmal volumes and did not show vortex shedding, although a recirculation zone was formed in the aneurysm, in which a vortex could be observed, that elongated and remained attached to the wall throughout the systolic portion of the cardiac cycle. To link the hemodynamics with aneurysm progression, the remodeling that occurred between week one and week two of the Ang II infusion was quantified and compared with the hemodynamic wall parameters. The strongest correlation was found between the remodeled distance and the oscillatory shear index, which had a correlation coefficient greater than 0.7 for all three models. These results demonstrate that the hemodynamics of the mouse AAA are driven by a strong shear layer, which causes the formation of a recirculation zone in the aneurysm cavity during the systolic portion of the cardiac waveform. The recirculation zone results in areas of quiescent flow, which are correlated with the locations of the aneurysm remodeling.     

Maximum Likelihood Analysis of Rare Binary Traits under Different Modes of Inheritance

Maximum likelihood methodology was applied to determine the mode of inheritance of rare binary traits with data structures typical for swine populations. The genetic models considered included a monogenic, a digenic, a polygenic, and three mixed polygenic and major gene models. The main emphasis was on the detection of major genes acting on a polygenic background. Deterministic algorithms were employed to integrate and maximize likelihoods. A simulation study was conducted to evaluate model selection and parameter estimation. Three designs were simulated that differed in the number of sires/number of dams within sires (10/10, 30/30, 100/30). Major gene effects of at least one SD of the liability were detected with satisfactory power under the mixed model of inheritance, except for the smallest design. Parameter estimates were empirically unbiased with acceptable standard errors, except for the smallest design, and allowed to distinguish clearly between the genetic models. Distributions of the likelihood ratio statistic were evaluated empirically, because asymptotic theory did not hold. For each simulation model, the Average Information Criterion was computed for all models of analysis. The model with the smallest value was chosen as the best model and was equal to the true model in almost every case studied.