Biomedical subjects

T M Goradia

Publications and source records attributed to T M Goradia.

5 recordsLinked to original sources

PubMed1992

Fast computation of genetic likelihoods on human pedigree data.

Gene mapping and genetic epidemiology require large-scale computation of likelihoods based on human pedigree data. Although computation of such likelihoods has become increasingly sophisticated, fast calculations are still impeded by complex pedigree structures, by models with many underlying loci and by missing observations on key family members. The current paper 'introduces' a new method of array factorization that substantially accelerates linkage calculations with large numbers of markers. This method is not limited to nuclear families or to families with complete phenotyping. Vectorization and parallelization are two general-purpose hardware techniques for accelerating computations. These techniques can assist in the rapid calculation of genetic likelihoods. We describe our experience using both of these methods with the existing program MENDEL. A vectorized version of MENDEL was run on an IBM 3090 supercomputer. A parallelized version of MENDEL was run on parallel machines of different architectures and on a network of workstations. Applying these revised versions of MENDEL to two challenging linkage problems yields substantial improvements in computational speed.

Algorithms↗

PubMed1991

Ordering three DNA polymorphisms on human chromosome 3 by sperm typing.

Three loci on the short arm of human chromosome 3 were ordered by sperm typing to expand the limited genetic map of this region. Almost 300 individual sperm from a donor triply heterozygous at D3S2, D3S11, and D3S12 were amplified by PCR using primers flanking the polymorphic site at each locus. Primary PCR product was reamplified using allele-specific primers of different lengths, allowing the allelic state at each locus to be determined by gel electrophoresis. Maximum likelihood analysis of the sperm-typing data showed that the most likely order was D3S2-D3S11-D3S12 with an odds ratio of almost 5000:1 when compared to the next most likely order. This finding should be useful in interpreting loss of heterozygosity on 3p in a variety of cancers. Our results also demonstrate the practicality of ordering DNA polymorphisms using sperm typing.

Alleles↗

PubMed1990

Multilocus ordering strategies based on sperm typing.

Sperm typing is a promising new approach for fine-structure human gene mapping. We examine three-locus sperm typing and its implications for the estimation of recombination fractions and for locus ordering. In particular, we compare some sequential stopping rules for three-locus assignment and develop methods for approximating their mean stopping times and error probabilities. A stopping rule recently described by Thompson and Boehnke et al. appears to be nearly optimal. Under this rule, one stops sampling as soon as the number of sperm of the least frequent recombinant type is s fewer than the number of sperm of the next least frequent type. We develop a random-walk algorithm and some heuristic formulas for assessing the performance of this rule. Since the broader goal of linkage analysis is to order many more than three loci, we propose a trisection strategy for ordering a new locus relative to an existing ordered set of loci. The crux of the trisection strategy is to restrict attention to the smallest block of ordered loci among which the new locus can fall and to divide this block into thirds for the next comparison. This trisection strategy is optimal in the sense that it has the best worse-case performance of any strategy. When it is applied sequentially to order a collection of loci, it is only nearly optimal, as we demonstrate by specific counter-example. However, it does become asymptotically optimal as the size of the collection increases.

Chromosome Mapping↗

PubMed1989

Single-sperm typing: determination of genetic distance between the G gamma-globin and parathyroid hormone loci by using the polymerase chain reaction and allele-specific oligomers.

The frequency of recombination between the G gamma-globin (HBG2) and parathyroid hormone (PTH) loci on the short arm of human chromosome 11 was estimated by typing greater than 700 single-sperm samples from two males. The sperm-typing technique employed involves the polymerase chain reaction and allele-specific oligonucleotide hybridization. Our maximum likelihood recombination fraction estimate of 0.16 (95%) confidence interval, 0.13-0.19) falls well within previous estimates based on family studies. With current technology and a sample size of 1000 sperm, recombination fractions down to approximately 0.009 can be estimated with statistical reliability; with a sample size of 5000 sperm, this value drops to about 0.004. Reasonable technological improvements could result in the detection of recombination frequencies less than 0.001.

Alleles↗

PubMed1987

An algorithm for automatic genotype elimination.

Automatic genotype elimination algorithms for a single locus play a central role in making likelihood computations on human pedigree data feasible. We present a simple algorithm that is fully efficient in pedigrees without loops. This algorithm can be easily coded and has been instrumental in greatly reducing computing times for pedigree analysis. A contrived counter-example demonstrates that some superfluous genotypes cannot be excluded for inbred pedigrees.

Algorithms↗