Biomedical subjects
Publications and source records attributed to S A Bacanu.
Although a portion of risk for late-onset AD (LOAD) is attributable to APOE, the search for other loci is ongoing. The authors hypothesize that psychotic symptoms with LOAD (LOAD+P) identify a potentially more etiologically homogeneous form of AD. Linkage analysis of families with LOAD+P identified one significant and several suggestive novel linkage signals, which bolsters the conjecture of greater etiologic homogeneity.
Large, population-based samples and large-scale genotyping are being used to evaluate disease/gene associations. A substantial drawback to such samples is the fact that population substructure can induce spurious associations between genes and disease. We review two methods, called genomic control (GC) and structured association (SA), that obviate many of the concerns about population substructure by using the features of the genomes present in the sample to correct for stratification. The GC approach exploits the fact that population substructure generates "over dispersion" of statistics used to assess association. By testing multiple polymorphisms throughout the genome, only some of which are pertinent to the disease of interest, the degree of overdispersion generated by population substructure can be estimated and taken into account. The SA approach assumes that the sampled population, although heterogeneous, is composed of subpopulations that are themselves homogeneous. By using multiple polymorphisms throughout the genome, this "latent class method" estimates the probability sampled individuals derive from each of these latent subpopulations. GC has the advantage of robustness, simplicity, and wide applicability, even to experimental designs such as DNA pooling. SA is a bit more complicated but has the advantage of greater power in some realistic settings, such as admixed populations or when association varies widely across subpopulations. It, too, is widely applicable. Both also have weaknesses, as elaborated in our review.
Although association analysis is a useful tool for uncovering the genetic underpinnings of complex traits, its utility is diminished by population substructure, which can produce spurious association between phenotype and genotype within population-based samples. Because family-based designs are robust against substructure, they have risen to the fore of association analysis. Yet, if population substructure could be ignored, this robustness can come at the price of power. Unfortunately it is rarely evident when population substructure can be ignored. Devlin and Roeder recently have proposed a method, termed "genomic control" (GC), which has the robustness of family-based designs even though it uses population-based data. GC uses the genome itself to determine appropriate corrections for population-based association tests. Using the GC method, we contrast the power of two study designs, family trios (i.e., father, mother, and affected progeny) versus case-control. For analysis of trios, we use the TDT test. When population substructure is absent, we find GC is always more powerful than TDT; furthermore, contrary to previous results, we show that as a disease becomes more prevalent the discrepancy in power becomes more extreme. When population substructure is present, however, the results are more complex: TDT is more powerful when population substructure is substantial, and GC is more powerful otherwise. We also explore general issues of power and implementation of GC within the case-control setting and find that, economically, GC is at least comparable to and often less expensive than family-based methods. Therefore, GC methods should prove a useful complement to family-based methods for the genetic analysis of complex traits.
OBJECTIVES: To evaluate the incidence of, and risk factors for, complications of endomyocardial biopsy in children. BACKGROUND: Endomyocardial biopsy (EMB) is a low risk procedure in adults, but there is a paucity of data with regard to performing this procedure in children. METHODS: Retrospective review of the morbidity and mortality of 1,000 consecutive EMB procedures. RESULTS: One thousand EMB procedures (right ventricle 986, left ventricle 14) were performed on 194 patients from July 1987 through March 1996. Indications for EMB included heart transplant rejection surveillance (846) and the evaluation of cardiomyopathy or arrhythmia for possible myocarditis (154). Thirty-seven (4%) procedures were performed on patients receiving intravenous inotropic support. There was one biopsy related death, secondary to cardiac perforation, in a two-week-old infant with dilated cardiomyopathy. There were nine perforations of the right ventricle, eight occurring in patients with dilated cardiomyopathy and one in a transplant recipient. The transplant patient did not require immediate intervention; two patients required pericardiocentesis alone, and six underwent pericardiocentesis and surgical intervention. All nine perforations were from the femoral venous approach (p < 0.01). Multivariate analysis demonstrated that the greatest risk of perforation occurred in children being evaluated for possible myocarditis (p = 0.01) and in those requiring inotropic support (p < 0.01). Other complications included arrhythmia (5) and single cases of coronary-cardiac fistula, flail tricuspid leaflet, pneumothorax, hemothorax, endocardial stripping and seizure. CONCLUSIONS: Risk of endomyocardial biopsy is highest in sick children with suspected myocarditis on inotropic support. However, EMB can be performed safely with very low morbidity in pediatric heart transplant recipients.