Haplotype association analysis for late onset diseases using nuclear family data

In haplotype-based association studies for late onset diseases, one attractive design is to use available unaffected spouses as controls (Valle et al. [1998] Diab. Care 21:949–958). Given cases and spouses only, the standard expectation-maximization (EM) algorithm (Dempster et al. [1977] J. R. Stat. Soc. B 39:1–38) for case-control data can be used to estimate haplotype frequencies. But often we will have offspring for at least some of the spouse pairs, and offspring genotypes provide additional information about the haplotypes of the parents. Existing methods may either ignore the offspring information, or reconstruct haplotypes for the subjects using offspring information and discard data from those whose haplotypes cannot be reconstructed with high confidence. Neither of these approaches is efficient, and the latter approach may also be biased. For case-control data with some subjects forming spouse pairs and offspring genotypes available for some spouse pairs or individuals, we propose a unified, likelihood-based method of haplotype inference. The method makes use of available offspring genotype information to apportion ambiguous haplotypes for the subjects. For subjects without offspring genotype information, haplotypes are apportioned as in the standard EM algorithm for case-control data. Our method enables efficient haplotype frequency estimation using an EM algorithm and supports probabilistic haplotype reconstruction with the probability calculated based on the whole sample. We describe likelihood ratio and permutation tests to test for disease-haplotype association, and describe three test statistics that are potentially useful for detecting such an association. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50656/1/20139_ftp.pd

An insight into the suspected HbA2' cases detected by high performance liquid chromatography in Pakistan

Background:Hemoglobin A2\u27 (delta 16 Gly Arg) is globally the commonest delta chain variant of HbA2. It is clinically and hematologically silent but its sole importance lies in the underestimation of HbA2 quantity during the workup of beta-thalassaemia trait. High performance liquid chromatography (HPLC) identifies it as a small S-window peak with a mean retention time of 4.59 0.03 minutes. This study aims at describing the frequency of detection of HbA2\u27 by HPLC in Pakistan and its confirmation at a molecular level. Potential HbA2\u27 cases were identified by a retrospective review of 10186 HPLC chromatograms in year 2006. Prospective samples were collected for polymerase chain reaction (PCR) amplification, restriction digestion and nucleotide sequencing. Findings: One hundred and ninety two potential cases (1.89%) of HbA2\u27 were detected on HPLC, having mean retention time of 4.59 0.05 minutes. Sixty four (0.6%) new cases were suspected of having co-existing beta-thalassaemia trait when the quantity of S-window peaks was taken into account. Thirteen samples with presumed HbA2\u27 on HPLC were subjected to molecular analysis and the said mutation (delta 16 GGC CGC) was not detected in any sample. Conclusion: It is concluded that diagnosis of HbA2\u27 on HPLC alone is not justified, as evidence of the presence of this delta chain variant in Pakistani population is yet to be proven. Such small S-window peaks should be either disregarded or confirmed at molecular level, and only then should influence the diagnosis of beta-thalassaemia trait. Further studies are required to determine the true nature of these peaks

Genetic analysis of an H-2 mutant, B6.C-H-2 ba , using cell-mediated lympholysis: T- and B-cell dictionaries for histocompatibility determinants are different

B6.C-H-2 ba [H (z1)] is a mutant derived from C57BL/6. The two strains mutually reject their skingrafts and are incompatible in the mixed leucocyte reaction (MLR) and in cell-mediated lympholysis (CML) assays. They are serologically indistinguishable.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46732/1/251_2005_Article_BF01564084.pd

Ceppellini, Ruggero -- 1959 -- Correspondence, Individual -- letter, 1959-02-10

Letter from Ceppellini, R. to Sabin, Albert B. dated 1959-02-10.Sabin Collection Fair Use Policy</a

Ceppellini, Ruggero -- 1959 -- Correspondence, Individual -- letter, 1959-01-09

Letter from Ceppellini, R. to Sabin, Albert B. dated 1959-01-09.Sabin Collection Fair Use Policy</a

L'emoglobina normale lenta A₂: suoi rapporti con una nuova frazione emoglobinica lenta, B₂, e sua importanza per il riconoscimento di varianti talassemiche che compaiono nelle famiglie di portatori di<i>Thalassemia media</i>e di emoglobinopatia H

SUMMARY1) An increase of hemoglobin A2over 3% is regarded as one of the two fundamental manifestations of the commonest thalassemic mutant in the heterozygous condition i.e. thalassemia minima ortypical microcytemia(here indicated asMA), while the other element is represented by the characteristic ensemble of the morphological and functional alterations of the erythrocytes. This assumption is based on the fact that the infrequent cases of sharp dissociation between the two elementsi.e.i) red cells normality with A2above 3 % (mA), andii) microcytemia with normal levels of A2(Ma). run in families and cannot be easily explained as a partial manifestation of a typical microcytemic gene.2) The unilocal origin of theMavariant seems to be well proved by the segregations from 5Ma×ma(normal) matings where 10Maand 9machildren have been observed. Moreover this variant has been detected among the relatives of a carrier of Hb H, born from aMa×mamating. This is in agreement with other recently published reports and strongly suggests that the relationship between Hb H andatypical microcytemia(with low A2) has a precise etiological significance.3) The unilocal origin of themAvariant (normocytic thalassemia?) is at the moment less firmly established. However a family is described (matingmA×MA) where the father and one child show the samemAphenotype; moreover one other child is affected by constitutional microcytic anemia (Th. media). This finding supports the observations of Silvestroni and Bianco, who have already reported that a number of patients with intermediate thalassemic syndromes are born frommA×MAmatings.4) At the moment no data exist which enable to decide whether the different thalassemias are mutations of the same or of different loci; however if they shall be shown to be allelic, the hypothesis must be kept in mind that the Thalassemia locus is a complex locus with more than one mutation sides, responsible for different but correlated aspects of the phenotype (red cell structure and A2level).5) The new hemoglobin B2, is described which has been recently identified by Kunkel. Ceppellini, Dunn and Firsheim (unpublished data). Reasons are given for regarding B2as the product of a mutation at the locus which is responsable for the synthesis of A2(locusHb2), The relationship of allelism between A2and B2is a proof of the genetic heterogeneity of the hemoglobin of the normal adult and may be taken as a model suggesting the genetic heterogeneity of hemoglobin A, notwithstanding its apparent chemical omogeneity.6) It is concluded that the conditions generally indicated as Thalassemias represent a genetically heterogeneous group, which have nonetheless to do with related metabolic processes. It is therefore suggested that the termThalassemiamay be mantained for indicating all hereditary defects which directly interfere with hemoglobinogenesis although not producing a specific abnormal hemoglobin.</jats:p

Ceppellini, Ruggero -- 1959 -- Correspondence, Individual -- letter, 1959-08-03

Letter from Ceppellini, R. to Sabin, Albert B. dated 1959-08-03.Sabin Collection Fair Use Policy</a