The role of renin-angiotensin-aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P=0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM

Actors and networks or agents and structures: towards a realist view of information systems

Actor-network theory (ANT) has achieved a measure of popularity in the analysis of information systems. This paper looks at ANT from the perspective of the social realism of Margaret Archer. It argues that the main issue with ANT from a realist perspective is its adoption of a `flat' ontology, particularly with regard to human beings. It explores the value of incorporating concepts from ANT into a social realist approach, but argues that the latter offers a more productive way of approaching information systems

Die Gestaltung von Sozialexperimenten: The good, the bad and the ugly

It is widely agreed that randomized controlled trials - social experiments - are the gold standard for evaluating social programs. There are, however, many important issues that cannot be tested using social experiments, and often things go wrong when conducting social experiments. This paper explores these issues and offers suggestions on ways to deal with commonly encountered problems. Social experiments are preferred because random assignment assures that any differences between the treatment and control groups are due to the intervention and not some other factor; also, the results of social experiments are more easily explained and accepted by policy officials. Experimental evaluations often lack external validity and cannot control for entry effects, scale and general equilibrium effects, and aspects of the intervention that were not randomly assigned. Experiments can also lead to biased impact estimates if the control group changes its behavior or if changing the number selected changes the impact. Other problems with conducting social experiments include increased time and cost, and legal and ethical issues related to excluding people from the treatment. Things that sometimes go wrong in social experiments include programs cheating on random assignment, and participants and/or staff not understanding the intervention rules. The random assignment evaluation of the Job Training Partnership Act in the United States is used as a case study to illustrate the issues

BIO FOr CARE: biomarkers of hypertrophic cardiomyopathy development and progression in carriers of Dutch founder truncating MYBPC3 variants—design and status

Background: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. HCM is an important cause of sudden cardiac death; however, overall prognosis is good and penetrance in genotype-positive individuals is incomplete. The underlying mechanisms are poorly understood and risk stratification remains limited. Aim: To create a nationwide cohort of carriers of truncating MYBPC3 variants for identification of predictive biomarkers for HCM development and progression. Methods: In the multicentre, observational BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort, carriers of the c.2373dupG, c.2827C > T, c.2864_2865delCT and c.3776delA MYBPC3 variants are included and prospectively undergo longitudinal blood collection. Clinical data are collected from first presentation onwards. The primary outcome constitutes a composite endpoint of HCM progression (maximum wall thickness ≥ 20 mm, septal reduction therapy, heart failure occurrence, sustained ventricular arrhythmia and sudden cardiac death). Results: So far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been included. HCM was diagnosed in 169 subjects and dilated cardiomyopathy in 4. The primary outcome was met in 115 subjects. Blood samples were collected from 131 subjects. Conclusion: BIO FOr CARe is a genetically homogeneous, phenotypically heterogeneous cohort incorporating a clinical data registry and longitudinal blood collection. This provides a unique opportunity to study biomarkers for HCM development and prognosis. The established infrastructure can be extended to study other genetic variants. Other centres are invited to join our consortium

Bayesian Statistical Identification of Orthotropic Elastic Constants Accounting for Measurement and Modeling Errors

International audienceBayesian identification provides a framework that can handle both measurement and modeling errors. Furthermore it identifies a probability distribution function thus providing information on both variance and correlation of the identified properties. However, the procedure can be very costly computationally. In order to address the computational cost issue a Bayesian identification procedure based on response surface methodology is proposed. The procedure is illustrated on the problem of identifying orthotropic elastic constants from natural frequencies of a free composite plate. The procedure accounts for measurement noise, uncertainty in other input parameters to the vibration model (plate dimensions, density) as well as systematic error effects. The joint probability distribution of the four elastic ply constants is identified and characterized by mean value and variancecovariance matrix. We find that some properties, such as Poisson's ratio, are identified with much higher uncertainty than other and that significant correlation between the identified properties is present. The developed procedure allowed substantial reduction in computational cost. However, in spite of the cost reduction techniques, it remains at the edge of what is presently reasonable computation time