The Sib TDT adjusted for age of disease onset.
Since the Sib-TDT (Spielman & Ewens, 1998) ignores age of disease onset, there could be loss of power in detecting linkage. In this article, we propose an adjustment for age of onset using the Cox Proportional Hazard Model (Cox, 1972) with the marker allele as a covariate. The test statistic for linkage is identical to the traditional Sib-TDT. Monte-Carlo simulations are performed under different disease models to assess the increase in power of the age-adjusted Sib-TDT compared to the traditional Sib-TDT. We extend our method to multiallelic markers. An application using data on Alzheimer's Disease is also presented.

title: Identifying rare variants from exome scans: the GAW17 experience
abstract: Genetic Analysis Workshop 17 (GAW17) provided a platform for evaluating existing statistical genetic methods and for developing novel methods to analyze rare variants that modulate complex traits. In this article, we present an overview of the 1000 Genomes Project exome data and simulated phenotype data that were distributed to GAW17 participants for analyses, the different issues addressed by the participants, and the process of preparation of manuscripts resulting from the discussions during the workshop.

title: A novel non-parametric regression reveals linkage on chromosome 4 for the number of externalizing symptoms in sib-pairs.
abstract: In this report, we present results of a genome-wide linkage scan using as a phenotype the number of externalizing symptoms associated with alcohol use disorders. Subjects were collected by the Collaborative Study on the Genetics of Alcoholism project from families in which at least three first degree relatives were affected by alcohol dependence. We use a novel non-parametric regression method based on kernel smoothing for our analysis. We report a statistically significant linkage close to the ADH gene cluster on Chromosome 4. We also obtain evidence for epistatic interaction between a region on Chromosome 1 and one on Chromosome 15. Although alcoholism as a covariate does not have any effect on the linkage scan, it has an effect on the epistatic interaction.

title: Linkage mapping of a complex trait in the New York population of the GAW14 simulated dataset: a multivariate phenotype approach
abstract: Multivariate phenotypes underlie complex traits. Thus, instead of using the end-point trait, it may be statistically more powerful to use a multivariate phenotype correlated to the end-point trait for detecting linkage. In this study, we develop a reverse regression method to analyze linkage of Kofendrerd Personality Disorder affection status in the New York population of the Genetic Analysis Workshop 14 (GAW14) simulated dataset. When we used the multivariate phenotype, we obtained significant evidence of linkage near four of the six putative loci in at least 25% of the replicates. On the other hand, the linkage analysis based on Kofendrerd Personality Disorder status as a phenotype produced significant findings only near two of the loci and in a smaller proportion of replicates.

title: A quantile-based method for association mapping of quantitative phenotypes: an application to rheumatoid arthritis phenotypes
abstract: Genetic association of population-based quantitative trait data has traditionally been analyzed using analysis of variance (ANOVA). However, violations of certain statistical assumptions may lead to false-positive association results. In this study, we have explored model-free alternatives to ANOVA using correlations between allele frequencies in the different quantile intervals of the quantitative trait and the quantile values. We performed genome-wide association scans on anti-cyclic citrullinated peptide and rheumatoid factor-immunoglobulin M, two quantitative traits correlated with rheumatoid arthritis, using the data provided in Genetic Analysis Workshop 16. Both the quantitative traits exhibited significant evidence of association on Chromosome 6, although not in the human leukocyte antigen region which is known to harbor a major gene predisposing to rheumatoid arthritis. We found that while a majority of the significant findings using the asymptotic thresholds of ANOVA was not validated using permutations, a relatively higher proportion of the significant findings using the asymptotic cut-offs of the correlation statistic were validated using permutations.

title: Integrating sibship data for mapping quantitative trait loci.
abstract: Sibship methods have been shown to be more powerful than traditional sib-pair methods in mapping quantative trait loci. We propose a statistical procedure which integrates data on sibships into a so-called 'contrast function', a natural extension of the classical squared sib-pair trait difference proposed by Haseman & Elston (1972). We also develop a combined mean and contrast function which provides more information on linkage compared to the contrast function. Our method is extended to multiple, epistatically interacting trait loci. Monte-Carlo simulations are included to compare the efficiencies of the proposed procedures with some currently used methods. An application of our proposed method is presented using data on alcohol dependence.

title: Interference in free thyroxine immunoassay.
abstract: We report two patients who presented with non-specific symptoms of tiredness that prompted their clinician to order a thyroid function test. In both cases, free thyroxine (T4) was reported to be high, with a normal thyroid-stimulating hormone (TSH). Repeated blood tests from the same laboratory using the same assay method yielded similar results. Due to discrepancies between the clinical and laboratory findings, we decided to repeat the blood tests at another laboratory using a different assay method. This revealed normal free T4 and TSH levels, suggesting that heterophile antibodies were interfering with the free T4 assay, leading to clinical confusion.

title: Application of L1-Norm Regularization to Epicardial Potential Solution of the Inverse Electrocardiography Problem
abstract: The electrocardiographic inverse problem of computing epicardial potentials from multi-electrode body-surface ECG measurements, is an ill-posed problem. Tikhonov regularization is commonly employed, which imposes penalty on the L2-norm of the potentials (zero-order) or their derivatives. Previous work has indicated superior results using L2-norm of the normal derivative of the solution (a first order regularization). However, L2-norm penalty function can cause considerable smoothing of the solution. Here, we use the L1-norm of the normal derivative of the potential as a penalty function. L1-norm solutions were compared to zero-order and first-order L2-norm Tikhonov solutions and to measured ‘gold standards’ in previous experiments with isolated canine hearts. Solutions with L1-norm penalty function (average relative error [RE] = 0.36) were more accurate than L2-norm (average RE = 0.62). In addition, the L1-norm method localized epicardial pacing sites with better accuracy (3.8 ± 1.5 mm) compared to L2-norm (9.2 ± 2.6 mm) during pacing in five pediatric patients with congenital heart disease. In a pediatric patient with Wolff–Parkinson–White syndrome, the L1-norm method also detected and localized two distinct areas of early activation around the mitral valve annulus, indicating the presence of two left-sided pathways which were not distinguished using L2 regularization.

title: Molecular characterization of a porcine Group A rotavirus strain with G12 genotype specificity
abstract: A porcine Group A rotavirus strain (RU172) was detected and molecularly characterized during a surveillance study conducted for rotavirus infection in a pig farm located in a suburban area of Kolkata City, India. The G12 genotype specificity of RU172 was revealed by PCR-based genotyping assays following addition of a G12 type-specific primer (designed in our laboratory to pick up G12 isolates from field samples) and was confirmed by sequence analysis of the VP7-encoding gene. The RU172 strain exhibited maximum VP7 identities of 93.6% to 94.5% with human G12 strains at the deduced amino acid level. In spite of its G12 genotype nature, RU172 appeared to be distinct from human G12 rotaviruses and, on phylogenetic analysis, formed a separate lineage with human G12 strains. Among the other gene segments analyzed, RU172 belonged to NSP4 genotype B, had a NSP5 and VP6 of porcine origin, and shared maximum VP4 identities with porcine P[7] rotaviruses (94.3%–95.4% at the deduced amino acid level). Therefore, to the best of our knowledge, this is the first report of detection of an animal rotavirus strain with G12 genotype specificity. Detection of strains like RU172 provides vital insights into the genomic diversity of Group A rotaviruses of man and animals.

title: Evidence for interstate transmission and increase in prevalence of bovine group B rotavirus strains with a novel VP7 genotype among diarrhoeic calves in Eastern and Northern states of India.
abstract: During a surveillance study (2003-2005) in a cattle market in Kolkata city, state of West Bengal, Eastern India, 34 (13.0%) of 260 calves with diarrhoea were positive for group B rotaviruses (GBR) by RNA electrophoresis in polyacrylamide gels. Analysis of the partial VP7 gene sequence of 28 of the 34 GBR strains revealed maximum identities (97.7-99.5% at nucleotide level and 97.8-100% at amino-acid level) with the novel bovine GBR 'Kolkata strains' reported in an earlier surveillance study (1.5%, n=192, 2001-2002) from the same cattle market, and shared low identities of 73.7-78.9% and 80.8-89.6%; 62.6-66.2% and 59.8-65.4%; 58.9-62.2% and 48.6-54.9% at nucleotide and amino-acid level with other bovine, human, and murine GBR. The GBR-infected calves were traced to districts in neighbouring states of West Bengal. Therefore, the present study reports a rapid increase in prevalence (13.0% in 2003-2005 against 1.5% in 2001-2002) of novel GBR strains among calves with diarrhoea, and provides evidence for interstate transmission of GBR.

title: Cloning of the p50 DNA binding subunit of NF-kappa B: homology to rel and dorsal.
abstract: The DNA binding subunit of the transcription factor NF-kappa B, p50, has been cloned. p50 appears to be synthesized as a larger protein that is then processed to its functional size. Sequence analysis reveals remarkable homology for over 300 amino acids at the amino-terminal end to the oncogene v-rel, its cellular homolog c-rel, and the Drosophila maternal effect gene dorsal. This establishes NF-kappa B as a member of the rel family of proteins, all of which display nuclear-cytosolic translocation. Protein sequence from the p65 polypeptide has established that it is not encoded in the same mRNA as p50. However, p65 appears homologous to c-rel, suggesting that c-rel may form heterodimers with p50 and rel may include a homodimerization motif.